Upload
others
View
5
Download
2
Embed Size (px)
Citation preview
S.I. : Genetic pathways to Neurodegeneration
Neurodegenerative diseases: model organisms, pathology and autophagy
SN Suresh1, Vijaya Verma2, Shruthi Sateesh2, James P Clement2,
Ravi Manjithaya1,2*
Molecular Biology and Genetics Unit1, Neuroscience Unit2, Jawaharlal Nehru
Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore 560 064
*Corresponding author: Ravi Manjithaya ([email protected])
Abstract
A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a
leading causative reason for damage seen at the cellular and organ level. While
investigative therapies that aim at dissolving aggregates have failed, and the promises
of silencing expression of ND associated pathogenic proteins or the deployment of
engineered iPSCs are still in the horizon, emerging literature suggests degrading
aggregates via autophagy related mechanisms hold the current potential for a possible
cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway
where superfluous or unwanted cellular cargoes (such as peroxisomes, mitochondria,
ribosomes, intracellular bacteria and misfolded protein aggregates) are wrapped in
double membrane vesicles called autophagosomes that eventually fuses with lysosomes
for their degradation. The selective branch of autophagy that deals with identification,
capture and degradation of protein aggregates is called aggrephagy. Here, we cover the
workings of aggrephagy detailing its selectivity towards aggregates. The diverse
cellular adaptors that bridge the aggregates with the core autophagy machinery in terms
of autophagosome formation are discussed. In ND, essential protein quality control
mechanisms fail as the constituent components also find themselves trapped in the
aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its
dysfunction further aggravates the pathogenesis. This phenomenon when combined
with the fact that neurons can neither dilute out the aggregates by cell division nor the
dead neurons can be replaced due to low neurogenesis, makes a compelling case for
aggrephagy pathway as a potential therapeutic option.
Introduction
Cellular homeostasis is achieved through a balance of anabolic and catabolic states.
Cells possess several quality control mechanisms to identify, correct or remove
dysfunctional or potential toxic cellular components such as proteins and organelles.
For example, inside cells, at steady state, misfolded proteins are formed continuously
and are fixed by chaperones or cleared via the ubiquitin proteasome system and
autophagy related pathways. This maintains the proteostatic equilibrium in cells.
Altered cellular states resulting from expression of pathogenic levels or mutant forms
of aggregate prone proteins overwhelm these quality control systems and their build-
up can eventually result in cell death. This is the fate of brain cells in neurodegenerative
diseases (NDD). In this review, we unravel this proteostatic central view as a cause for
ND, discuss the potential reasons behind the failure of quality control systems with an
emphasis on an aggrephagy, autophagy related pathway.
Proteostasis
Protein quality control machineries ensure the proper folding of newly synthesized
proteins for their distinct function. This process is critical as 30% of these new proteins
are prone to misfolding (Mymrikov et al., 2017). The cellular quality control measures
include unfolding, refolding and/or degradation of the misfolded proteins (Sontag et al.,
2017). Not surprisingly, failure of protein quality control poses a threat to the cellular
vitality (Balch et al., 2008). This qualitative process of maintaining the homeostasis of
intracellular pool of functional and “healthy” proteins is called proteostasis.
Proteostasis as a function for cell survival becomes even more critical for those cells
such as neurons that cannot divide and thus dilute out the toxic protein aggregates
(Balch et al., 2008). In addition, with age, the neuronal proteostatic machineries
become incompetent and prone for accumulation of damaged organelles and misfolded
proteins (Labbadia & Morimoto, 2015; Walther et al., 2017).
Protein misfolding is not an uncommon phenomenon inside cells. The presence of
misfolded protein activates chaperones to unfold and refold them in an ATP-dependent
manner. Misfolded proteins induce heat shock response (HSR) and heat shock (HS)
transcription factor HSF-1 that include the upregulation of heat shock cognate protein
(Hsc70) (Kampinga & Craig, 2010). The aim of enhancing chaperone expression and
its activity is to prevent protein aggregation. Once the proteins remain misfolded
despite the efforts by chaperones, they will form the higher order structures such as
oligomers and aggregates that will eventually accumulate inside cells. In certain
scenarios, when protein aggregates overwhelm the chaperone capacity, the available
chaperones themselves get trapped in protein aggregates (Anckar & Sistonen, 2011;
Raychaudhuri et al., 2014). Subsequently, these events also aggravate disease
pathogenesis. An additional mechanism that has been recently described identifies
misfolded proteins as early as they are translating and subsequently marks them for
degradation. Such nascent misfolded polypeptides are ubiquitinated at K-48 residue as
a degradation mark in a process termed as cotranslational ubiquitination (CTU) (Wang
et al., 2013). The polypeptide with this mark will be acted upon by proteasome for
their effective degradation. CTU happens within the active translation complexes
(Wang et al., 2013).
At the organellar level, accumulation of misfolded proteins inside endoplasmic
reticulum (ER) lumen induces ER stress, which triggers one of the vital cellular
adaptive mechanisms known as unfolded protein response (UPR) (Powers et al., 2009).
UPR leads to suppression of active protein translation, increase ER chaperone
accumulation to unfold and/or degrade these proteins to ameliorate the proteotoxicity
(Hetz, 2012). Post-mortem brain analyses of Alzheimer’s disease (AD), Parkinson’s
disease (PD) and Huntington’s disease (HD) have revealed the correlation of UPR
markers with protein aggregation and onset of disease pathogenesis (Hetz & Mollereau,
2014).
The fate of misfolded proteins, not refolded by chaperones, are marked for degradation
through ubiquitin-proteasome system (UPS) and/or autophagy. UPS degrades
ubiquitinated, soluble and short-lived proteins. The target protein is tagged by ubiquitin
through three enzymatic ubiquitin- activating (E1), - conjugating (E2) and –ligating
(E3) reactions (Goldberg, 2003). Ubiquitin is attached through its carboxyl residue to
specific lysine residue through isopeptide linkage. One ubiquitin molecule is a target
for another ubiquitin molecule and forms a polyubiquitin chain at its lysine residues at
48, 63 or at N-terminal methionine residue (Kirkin et al., 2009). The polyubiquitin
signal at K48 serves as a proteasome degradation signal whereas K63 and N-term
methionine signals serve other functions (Kirkin et al., 2009). It is also proposed that
K63 polyubiquitination may target a protein to autophagy, but the exact mechanism is
unclear.
UPS has been shown to degrade several neurodegenerative disease related proteins such
as tau, SOD1 and α-synuclein (Goldberg, 2003). Inhibiting UPS accumulate disease
related proteins to aggregate and form inclusion bodies inside cells. Thus, UPS is
essential for cells to prevent toxic protein aggregate formation (Lim & Yue, 2015). It
is believed that larger aggregates that cannot be resolved by UPS are the substrates of
the autophagy machinery.
Aggrephagy: definition and modes
In 1960s, the Nobel laureate Christian De Duve observed double membrane vesicles
entrapping intracellular organelles and proteins and coined the term “self-eating” or
autophagy (De Duve & Wattiaux, 1966). Nobel laureate Yoshinori Ohsumi tapped the
power of yeast genetics to elucidate the molecular mechanism governing autophagy
and contributed to the discovery of its conserved nature from yeast to mammals
(Harnett et al., 2017).
Depending on the distinct molecular mechanisms, autophagy is broadly classified into
three types: Macroautophagy, Microautophagy and Chaperone mediated autophagy
(CMA). Macroautophagy is the most extensively studied process that has an
indispensable role in maintaining cellular and organismal homeostasis. During
macroautophagy, a phagophore or isolation membrane forms and expands to form
double membrane autophagosomes that engulfs cellular cargoes. These cargoes are
parts of cytosol constituting superfluous organelles, pathogenic organisms, misfolded
protein aggregates and/or damaged mitochondria (Zaffagnini & Martens, 2016). These
autophagosomes fuse with lysosomes to form autolysosomes and eventually degrade
its intraluminal cargoes. The degraded entities result in building blocks that are recycled
back to the cytosol for fuelling other cellular pathways. Apart from randomly
sequestering portions of cytosol for degradation (general autophagy), macroautophagy
can be highly selective in the cargoes it captures. The selective autophagy pathway that
is involved in clearance of misfolded protein aggregates is called aggrephagy (Hyttinen
et al., 2014). Here, misfolded proteins that are tagged by ubiquitin are recognized by
adaptor proteins such as p62, NBR1 and NDP52 which in turn recruit autophagy
proteins such as LC3 to facilitate selective capture (Figure 1).
Thus, aggrephagy is a prominent defense mechanism against misfolded protein
aggregate mediated cellular toxicity. Microautophagy is the direct uptake of cargo by
lysosomes through membrane invagination. Chaperone Mediated Autophagy (CMA) is
the selective degradative process of proteins that involves Hsc70 but is a vesicle
independent process. During CMA, the target protein is recognized by Hsc70 through
a specific amino acid motif, KFERQ and delivered to lysosome by interacting with
LAMP2A in an ATP-dependent manner.
Synaptic dysfunction in NDD
Synaptic plasticity refers to the ability of synapses to modify their structure and tonus
after persistent electrical activity and/or signalling. In fact, the number, morphology,
position, molecular phenotype, and strength of synapses continue to modify as a
function of neurons’ requirements. These events take place in the nervous system
during its development, which represents the basis for learning and memory (Bliss &
Collingridge, 1993; Citri & Malenka, 2008). In case of neurons, in addition to the
autophagy process in soma, autophagy occurring at the synapse, of late, has received
much attention as it involves immediate turnover of proteins and, thus, affects synaptic
transmission. Mutations in genes involved in several neurodegenerative diseases such
as Alzheimer, Huntington, ALS and Parkinson disease affect synaptic proteins levels
and functions (Lepeta et al., 2016). Synaptic dysfunction throughout the central and
peripheral nervous systems has shown to be an early hallmark of neurodegenerative
diseases preceding neuronal death and the subsequent onset of clinical symptoms
(Figure 2 and Table 1) (Brose et al., 2010). These events have been validated using
transgenic mouse models available for different neurodegenerative diseases
(Trancikova et al., 2011).
Neurodegeneration model systems as tools to study aggrephagy
Numerous model systems have been utilized to study the aggrephagy and modulate it
to clear the protein aggregates. It is important to note that the cellular proteostatic
machineries are conserved from simple yeast to higher model rodents. We will briefly
discuss the different model systems used to understand the neurodegeneration
pathogenesis with a special emphasis on autophagy.
Animal models to study NDD
Historically, mouse has been used as a model to study genetic mutation-causing
diseases in humans, especially brain related disorders including neurodegeneration
diseases, due to the similarity of mammalian neuronal physiology and anatomy to
human brain. The main rationale to model human disorders in non-human organisms is
the identification of fundamental pathogenic mechanisms that could lead to potential
novel therapeutic targets, and the elevation of efficacy and safety of potential drugs. A
prerequisite for clinical trials of a compound in humans is the successful alleviation of
the disease or symptoms in animal models.
The occurrence of neurodegeneration is majorly a sporadic event with poorly
understood etiological basis. However, in familial cases of AD, PD, HD and ALS, the
genetic mutations are the underlying causes of disease phenotypes and these can be
recapitulated in animal models. Due to a rapid increase in the availability of the type of
genetically modified mice (Branchi et al., 2003), it is critical to meticulously
characterise the biochemical, pathological and behavioural features of these mice and
compare them with human phenotypes (Crawley, 2008). Generally, laboratories
involved in testing the phenotypes of genetically modified mice subject these mice to a
battery of behavioural features to assess cognitive, motor and sensory functions. To
consider a genetically modified mouse as a disease model, it must fulfil three levels of
validity to judge its psychopharmacology (van der Staay et al., 2009). An animal model
should score high on the following validities: face validity, i.e., resemblances of
behavioural phenotypes of mouse model to that of human disorder; construct validity,
i.e., closely reconstructs and mimics the underlying cause of the disease or disorder;
and predictive validity, i.e., treatments alleviate symptoms in mouse and human. A
successful mouse model should fulfil face and construct validity before being tested for
therapeutics (Predictive validity). Due to these varied features and their behavioural
readouts, the mouse models of the respective human diseases are highly useful in NDD
research and in preclinical studies.
1. Parkinson disease (PD)
Parkinson disease (PD) is characterized by progressive degeneration of nigrostriatal
dopaminergic neurons, leading to loss of motor function, rigidity, postural instability,
tremor, and bradykinesia as described in the 1800’s by James Parkinson (Mhyre et al.,
2012; Rouse et al., 2000). Both familial (5–10% of all cases) and acquired (90–95% of
all cases) forms of Parkinsonism are usually caused by defects in dopamine (DA)
metabolism. Decrease in DA inputs from basal ganglia (BG) result in impaired control
of motor circuits that ultimately leads to clinical symptoms (Spillantini et al., 1997).
For the PD mouse model, the transgenics express pathogenic mutant version of PD
associated genes such as α-Synuclein, Parkin, Pink1 and Park7. α-Synuclein transgenic
mice exhibit Lewy bodies that are the histopathological hallmark of PD. These animals
exert age-related progressive movement deficits, which is associated with
dopaminergic neuronal loss. However, not all transgenic mutants exert significant
dopaminergic neuronal loss.
Activity-dependent modifications in synaptic efficacy, such as long-term depression
(LTD) and long-term potentiation (LTP) represent the key cellular substrates for
adaptive motor control and procedural memory (Bliss & Collingridge, 1993).
Dopamine (DA) acting on D1- and D2-like receptors play a critical role in driving the
above-mentioned forms of synaptic plasticity in striatum. D1 and D2 receptor signalling
pathways converge in opposite manners on a common target, DARPP-32. The
involvement of DA in these phenomena has been thoroughly established by the study
of synaptic plasticity in striatal neurons recorded from rodent models of PD (Calabresi
et al., 1992a; Calabresi et al., 1992b). The absence of synaptic plasticity and abnormal
synapse structure implied the cellular basis underlying the abnormalities in striatal
output within the Basal ganglia (BG), and consequently resulting in PD symptoms.
Abnormalities in the subcellular distribution of N-methyl-D-aspartate receptor
(NMDAR) subunit GRIN2B represent one of the major changes that take place at
corticostriatal glutamatergic synapses. In fact, studies using dyskinetic mouse models,
increased levels of GRIN2A and lower levels of GRIN2B were observed in extra
synaptic sites which altered binding of NMDAR subunits with their cargo proteins such
as Synapse-associated protein 97 (SAP97) and SAP102 (Gardoni et al., 2006; Sheng &
Sala, 2001). Moreover, activation of DARPP-32 (dopamine- and cAMP-regulated
phosphoprotein-32) results in increased opening of the L-type Ca2+ channels promoting
the transition of Medium Spiny Neurons (MSN) to a higher level of excitability, which
in turns phosphorylates AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid) and NMDARs providing a mechanism for the direct control of glutamatergic
transmission by DA signalling, that is altered in PD (Greengard et al., 1998; Vergara et
al., 2003). This is further evident from the studies that show the dopamine-denervation
augments neuronal excitability in the striatum leading to excitability of striatal neurons,
which is caused due to the increased glutamatergic cortical inputs to the striatum.
(Calabresi et al., 1993; Centonze et al., 2004). The increased glutamate level in the
synaptic cleft (Herrera-Marschitz et al., 1994), is consequently responsible for the
overactivity of NMDARs and AMPARs on MSNs which correlate with the motor
behaviour abnormalities observed in a rat model of PD. Thus, functional changes of the
striatal neurons may alter the output signals from the striatum to the other structures of
the basal ganglia that leads to pathophysiological changes observed in Parkinson's
disease.
Evidences also suggest that the genes linked to PD play a critical role in regulating
proper presynaptic and synaptic vesicular transport, modification of DA flow and
altered presynaptic plasticity (Dihanich & Manzoni, 2011). Once Parkinsonism is well
established, i.e. parkinsonian state, most BG mechanisms are insufficient and cortical
mechanisms become important (Blesa et al., 2017; Dihanich & Manzoni, 2011). At the
postsynaptic level, decreased activation of D2 receptors leads to a disinhibition of
voltage-gated ion channels and increased influx of Ca2+ that leads to degeneration of
the synapses observed in PD-affected animals and in PD patients (Arbuthnott et al.,
2000; Calautti et al., 2007; Nitsch & Riesenberg, 1995). In DA-denervated striatum,
NMDAR subunit GRIN1, and its interacting protein at synapse, PSD-95, levels are
selectively reduced in the post-synapse (Lundblad et al., 2004).
2. Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease
characterized by progressive loss of upper motor neurons in the motor cortex (cortical
layer of pyramidal cells of cortical layer V), and of lower motor neurons in the
brainstem and spinal cord as first described by Jean-Martin Charcot in 1869 (Kumar et
al., 2011). ALS typically affects adults in mid-life, with an incidence of 1–
2/100,000/year (Rosen, 1993). Most ALS patients have no affected family members
and are considered to have sporadic ALS. Familial ALS occurs in 5–10% of cases and
has an autosomal dominant inheritance. Mutations in genes such as TARDP (TDP-43),
FUS and SOD1 drive the familial forms of ALS. In 20% of familial cases, mutations in
the superoxide dismutase-1 (SOD1) gene on chromosome 21q were identified (ALS1)
(Rosen, 1993). The recessive, juvenile ALS2, is caused by mutations in ALSIN, which
codes for a protein containing guanine exchange factor domains (Hadano et al., 2001;
Yang et al., 2001). Mice transgenics overexpressing wild type or mutant TDP-43
proteins cause TDP-43 inclusion bodies and loss of motor neurons with behavioural
impairments. In addition, mice overexpressing mutant SOD-1 develops inclusion
bodies, neuronal loss, gliosis, tremor, hindlimb paralysis with significant reduction in
lifespan.
The pathological hallmark of ALS is the degeneration of lower motor neurons in the
brainstem and spinal cord, upper motor neurons in the motor cortex, and of the
corticospinal tracts, accompanied by reactive gliosis (Pehar et al., 2005). The exact
pathogenic mechanism underlying the selective motor neuron death in ALS is yet to be
elucidated, although many possible mechanisms in sporadic ALS, and SOD1-linked
ALS have been proposed (Brown & Robberecht, 2001; Cleveland & Rothstein, 2001;
Heath & Shaw, 2002; Julien, 2001). One of the common reasons for neuronal
degeneration is because of the overstimulation of glutamate receptors induced
excitotoxicity (Lipton & Rosenberg, 1994).
Evidences from the past studies have strengthened a link between glutamate-mediated
toxicity and sporadic ALS. Motor neurons express Ca2+-permeable AMPARs, GRIA2
subunit, and are, therefore, particularly vulnerable to AMPAR-mediated excitotoxicity
(von Lewinski & Keller, 2005). Transgenic mice expressing GRIA2 subunits with an
asparagine at the Q/R site (conferred a two-fold increase in the Ca2+ permeability of
AMPARs) (Feldmeyer et al., 1999), and showed late-onset of degeneration of spinal
neurons and a decline in motor function (Kuner et al., 2005). Crossing these mice with
those carrying a mutation linked to familial ALS accelerated disease progression and
motor decline (Kuner et al., 2005), and the phenotype is exaggerated when GRIA2 is
deleted (Van Damme et al., 2005).
The NMDAR-mediated neurotoxicity and subsequent overload of mitochondrial Ca2+
and ROS production has been shown to take place in cultured motor neurons (Carriedo
et al., 2000). Furthermore, the NMDAR/Ca2+ mediated excitotoxicity has been
demonstrated in the neuronal loss observed in spinal neurons obtained from human low
molecular weight Neuro filament (NF) protein (hNfl+/+) mice, an ALS mouse model
(Kambe et al., 2011; Nicholls et al., 2007; Sanelli et al., 2007). Compelling evidence
supports the fact that excessive Ca2+ influx through NMDARs targets mitochondria
which results in excitotoxicity in ALS-related MN death (Peng et al., 1998). It is
intriguing to hypothesize that regain control of the NMDAR functionality will in turn
affect AMPAR function, due to the close interaction between these receptors, thereby
further hampering the ALS-related excitotoxic drive.
Apart from the extensive loss of motor neurons, there is degeneration of midbrain
dopaminergic cells and reduced tyrosine hydroxylase positive neurons which has been
described in both familial and sporadic forms of ALS, (Andreassen et al., 2000; Kostic
et al., 1997), and functional alteration of the voltage-dependent Na2+ channel (Zona et
al., 1998). The dysfunction in the DA neurons is shown by investigating the
corticostriatal synaptic plasticity in mice overexpressing the human SOD1 and mutating
the (Gly933Ala) form (G93A) of the same enzyme(Calabresi et al., 2000; Lovinger et
al., 1993).
The pivotal role of DA in corticostriatal LTD is well established. For example, injection
of 6-hydroxydopamine in rodent model leads to DA denervation that modifies the
corticostriatal plasticity (Calabresi et al., 1992a; Calabresi et al., 1992b) . Moreover, a
decreased striatal D2 receptor binding in sporadic ALS has been described and is likely
to occur because of an excessive glutamatergic corticostriatal neurotransmission
(Vogels et al., 1999; Vogels et al., 2000). This pattern of degeneration is consistent
with the observation that elevated levels of SOD1 are expressed in basal ganglia cells,
including the midbrain dopaminergic neurons (Pardo et al., 1995). In conclusion,
perturbations in these systems may cause the cell to become more susceptible to
excitotoxic damage.
There is spectrum of synaptic changes that occur in ALS during the process of anterior
horn neuron degeneration. One such probable cause is due to the decreases in cell body
area, number of synapses, and synaptic contact length which is evident even during the
early stage of the disease. It is noteworthy that despite decreases in cell body area,
synaptic numbers and synaptic contact length, the length of the active zone was not
reduced in the normally appearing neurons of the ALS patients (Sasaki & Maruyama,
1994). The continuous loss of synapses that is observed from myriad studies implies a
decrease in the global connectivity of the motor system and a decreased potential for
motoneuronal interaction.
The neuromuscular junction (NMJ) is the synapse where the axon terminal of a motor
neuron (MN) meets the motor endplate. Recent studies suggest that distal degeneration
in the skeletal muscle plays a key role in the progression of ALS. Several studies using
SOD1G93A mice have shown that NMJ degeneration occurs in the initial stages of
disease progression, long before MN loss (Brooks et al., 2004; Fischer & Glass, 2010;
Kanning et al., 2010)
3. Huntington’s Disease (HD)
Huntington`s Disease (HD) is a progressive neurological disorder characterised by
chorea (uncontrolled dance like movement), cognitive disturbances, depression and
other psychiatric symptoms (Harper, 1996). It is inherited in an autosomal dominant
fashion, and severity of the disease depends on number of CAG repeats (Jones et al.,
1997; Walker, 2007). Both HTT and mutant HTT (mHTT) proteins are ubiquitously
expressed, predominantly in the striatum, although it is the least affected in HD, and in
moderate levels in other parts of the brain (Bhide et al., 1996). HTT is shown to be
expressed in the brain from midgestational period, and the expression of mHTT was
observed as early as 10-week old infant’s brain suggesting an implication for proper
neuronal development and function, especially when the brain is vulnerable to
excitotoxic injury (DiFiglia, 1997).
To further understand the function of HTT and mHTT in normal neuronal function and
in diseased states respectively, several mouse models of HD has been created (Cepeda
et al., 2010; Levine et al., 2004; Menalled & Brunner, 2014; Menalled & Chesselet,
2002). There are two types of mouse models of HD: ‘transgenics’, in which the mutant
gene or part of it, is inserted randomly into the mouse genome, leading to the expression
of mutant protein along with the endogenous normal HUNTINGTIN; and ‘knock-ins’,
in which the mutant gene is inserted into the mouse Hdh (mouse Huntington) gene,
leading to either homozygotes or heterozygotes for the mutation [for further
information please refer (Menalled & Brunner, 2014; Menalled & Chesselet, 2002)].
Myriad of transgenic mice with expanded polyQ repeats like R6/1, R6/2 and N171-Q82
have been generated that recapitulate the symptoms of HD. All these models develop
aggregate inclusions, neuronal loss and motor-coordination deficits. The first and most
widely used transgenic mouse model of HD was generated by overexpression of exon
1 of the human gene encoding HUNTINGTIN (IT15) with 141-157 CAG-repeat
expansions, which was termed as R6 (Mangiarini et al., 1996). Unlike Htt homozygous
knock-out (embryonically lethal but not Htt conditional Knock-out) (Nasir et al., 1995;
Wang et al., 2016), R6 mice survive for 13 weeks. Apart from the motor deficits, these
different mouse models exhibit altered synaptic function and cognitive deficits.
Research over many years suggests that cognitive defects appear long before the onset
of overt motor dysfunction in HD (Paulsen et al., 2008). These studies have shown that
synaptic dysfunction precedes cell death by many years in humans (Murer et al., 2002).
It is observed that loss of medium-shaped spiny (MSN) projection neurons in striatum,
and pyramidal neurons from cortex is considered as prominent pathological
characteristics of HD (Milnerwood et al., 2010; Milnerwood & Raymond, 2010;
Vonsattel et al., 1985).
Impaired dopamine homeostasis is one of the major consequences of HTT (including
Htt) mutation that contributes to the impaired information processing from the cortical
inputs to striatum (Andre et al., 2010). Dopaminergic neurons from substantia nigra
and ventral tegmental area (VTA) project to the dorsal striatum to regulate
glutamatergic neurons (direct pathway; rich in D1 receptors; facilitates movement),
whereas, indirect pathway projects to external globus pallidus (rich in D2 receptors;
suppresses movement) (Andre et al., 2010; Sepers & Raymond, 2014), which are found
to be degenerated in HD. On the contrary, Andre et al, have shown that hyperactivation
of the nigrostriatal pathway may elicit the characteristics of chorea observed in HD.
Therefore, agents affecting dopamine transmission are used to modulate HD (Murer et
al., 2002).
Proper glutamatergic function of these neurons is driven majorly by glutamate
(excitatory neurotransmitter), and, thus have an increased sensitivity towards NMDAR
activation leading to neuronal death, especially in HD (Fonnum et al., 1981; McGeer
et al., 1977; Schwarcz et al., 1983). By the time motor symptoms were observed,
majority of striatal glutamatergic neurons and spine densities were lost (Cepeda et al.,
2010; Cepeda et al., 2007; Li, 1999). Thus, reduced glutamatergic signalling in the
striatum could lead to loss of spines and, eventually, contribute to motor deficits.
To study the functional insights of HD pathology, electrophysiological studies have
dissected out intrinsic and synaptic neuronal properties (Sepers & Raymond, 2014).
Studies have shown that, in R6/2 mice, basal synaptic transmission and presynaptic
release were progressively altered (Cepeda et al., 2001; Khedraki et al., 2017; Klapstein
et al., 2001; Milnerwood et al., 2006). Presymptomatic R6/2 mice showed increased
neuronal input resistance and lower stimulus intensity to evoke action potentials
(rheobase), whereas, symptomatic R6/2 mice exhibited increased resting membrane
potentials, input resistance and decreased membrane time constants and synaptic
plasticity. Taken together, these findings indicate that passive and active membrane and
synaptic properties of medium-sized spiny neurons are altered in the R6/2 transgenic.
Many studies have observed an early augmentation of NMDAR activity in MSNs of
HD mouse (Cepeda et al., 2010; Cummings et al., 2010; Milnerwood & Raymond,
2007). Further, overexpression of GluN2B subunit in HD has been shown to exacerbate
the phenotype and pathology. Studies have shown that brief stimulation of synaptic
NMDAR (containing GluN1/GluN2A) leads to survival signalling via BNDF activation
(Martire et al., 2013) but activation of extrasynaptic NMDAR (containing
GluN1/GluN2B) is neurotoxic and leads to cell death (Hardingham et al., 2002). These
studies suggest that hyperactivation of extrasynaptic NMDAR leads to neuronal loss in
HD.
In another mouse model of HD, Yeast Artificial Chromosome (YAC)-Htt (YAC128),
containing entire human HTT to have 128 CAG-repeat expansions (Slow et al., 2003),
it was found that the probability of release at D1-presynapse was increased in 1.5
months, but decreased at 12 months. However, D2-presynapse release probability was
not altered in these mice (Cummings et al., 2010). Further studies have shown that the
synaptic transmission and function are altered in YAC128 mouse model of HD (Joshi
et al., 2009; Miller et al., 2008). Similar observations were found in other mouse
models of HD (Akopian et al., 2016; Cummings et al., 2010; Graham et al., 2009;
Klapstein et al., 2001; Kolodziejczyk & Raymond, 2016; Levine et al., 2004; Levine
et al., 1999; Pouladi et al., 2009).
4. Alzheimer`s Disease (AD)
Alzheimer`s Disease (AD) is the most common cause of senile dementia and a
devastating neurodegenerative disease. Formation of senile plaques, neurofibrillary
tangles (NFT), massive loss of synapses, and eventual neuronal cell death are the
pathological hallmarks of AD. The pathogenesis is associated with increased β-amyloid
(Aβ) levels in the brain generated by proteolysis of amyloid precursor protein (APP)
with the help of Presenilin1 (PSEN1), and part of γ- secretase complex (De Strooper
et al., 1998; Selkoe, 2002). Mutations in APP and Presenilin1 or 2 genes result in an
autosomal dominant form of AD. To understand the mechanism of AD, temporal
evolution, and to translate it for therapeutic purposes, several transgenic mouse models
of AD has been used till date. There are currently 127 animal models of AD in use
having wide variety of mutations (single, double and triple mutations) that are
implicated in AD [(Higgins & Jacobsen, 2003; LaFerla & Green, 2012)
www.alzforum.org]. Recently, very robust mouse model, 5xFAD, having five familial
AD mutations, causes relatively early and aggressive presentation of AD, has been
widely used as compared to other models. It recapitulates the following disease
phenotypes: β-amyloidosis, plaques, neurite dystrophy, dendritic spine loss,
neuroinflammation, neuronal loss and age-dependent cognition decline. Limitations of
these models include the following: a) evidences from positron-emission tomography
(PET) suggest that mouse plaques are significantly differ from human biochemically,
and b) another caveat is the neuronal loss is not profound as that of humans (Sasaguri
et al., 2017). A detailed review on various animal models of AD can reviewed here
(LaFerla & Green, 2012; Pozueta et al., 2013; Sasaguri et al., 2017). These transgenic
models show synaptic dysfunction, and, thus, provide an opportunity to understand the
mechanisms of neurophysiological deficits observed in AD, mainly the synaptic and
cognitive decline (Rowan et al., 2003; Spires-Jones & Knafo, 2012). Abnormalities in
synaptic function in AD was observed more than four decades ago by Gonatas et al
(Gonatas et al., 1967). Since then, there are many studies that focused on reinforcing
the idea that loss of synaptic function is the main characteristics of AD. Indeed, this
was further confirmed by quantitative ultrastructural and immunohistochemical post-
mortem studies from human AD patients with symptoms ranging from mild-cognitive
impairments to early-mild AD (Masliah et al., 1989; Scheff & Price, 1993; Terry et al.,
1991). Most of the electrophysiological studies of amyloid depositing mouse models
have investigated alterations in synaptic strength between hippocampal pyramidal
neurons by measuring basal synaptic strength, synaptic transmission, and neuronal
intrinsic properties (Nistico et al., 2012). A study from a mouse model of AD
expressing single or double transgenic mutations showed normal basal synaptic
transmission but impaired LTP in early stage of AD (Liu, 2008), while in another study
using App695Swe mutation, normal LTP with deficits in basal synaptic transmission was
observed for both 12- as well as 18-month old mice (Fitzjohn et al., 2001). These initial
studies have shown that disruption in synaptic function is the major cause of cognitive
decline in AD. Studies have shown that AD pathology increases in an age dependant
manner (Hsia et al., 1999; Sun et al., 2017). By using Apoe4 mouse (4 months and
older), alteration in short as well as long-term plasticity has been observed (Sun et al.,
2017). A similar age dependent decline in basal synaptic function was observed in other
models (Hsia et al., 1999; Puzzo et al., 2017). These studies clearly show that the
decline in basal synaptic function is an early indicator cognitive decline observed in
later stages of AD. To further understand whether amyloidogenic processing of APP is
responsible for Amyloid Beta and Tau toxicity, toxic proteins are administered in acute
brain slices prepared from WT as well as BACE1 KO mice. No affect in basal synaptic
transmission was observed in WT or BACE1 (β Secretase) KO mice but LTP was
impaired in both genotypes, suggesting toxicity did not depend on APP processing
alone (Puzzo et al., 2017). Apart from the alterations in synaptic function, abnormal
dendritic spine structures were also observed in AD. Dendritic spines are specialised
anatomical structures on neuronal cells that serve as the postsynaptic component for the
excitatory dendritic spines. Several studies using different mouse models of AD have
identified severe dendritic spine loss and plaque-associated structural plasticity deficits
in AD. This is extensively reviewed here (Pozueta et al., 2013; Rowan et al., 2003;
Spires-Jones & Knafo, 2012). Based on these studies, basal synaptic function can be
used as a biomarker to detect AD in an early stage of development.
Drosophila melanogaster
It is a multicellular eukaryote that exhibits both histological and behavioural phenotype
associated with neurodegeneration. Flies expressing the proteins such as α-synuclein,
β-amyloid, polyglutamine repeat, tau recapitulate many of the histological and
behavioural disease phenotypes associated with neurodegeneration. In this model, the
toxic proteins are overexpressed in retina leading to rough-eye phenotype that forms a
platform, which is used extensively for genetic and chemical screens (Luheshi et al.,
2007). The advantages working with flies are short doubling time, multicellularity,
availability of genetic resources and ability to express proteins in a tissue-specific
manner. Also, the fly model can unravel the basic pathophysiological mechanisms
underlying neurodegeneration. It is often used synergistically with another disease
model to validate the basic mechanisms. For e.g. a small molecule screen performed
on fly model identified mGLUR5 (GPCR) as a druggable target that is abundantly
expressed in brain (Chang et al., 2008). Recently, regulation of protein QPCT
(glutaminyl cyclase) has been shown to curb neurodegeneration symptoms in fly model
and mammalian cells (Jimenez-Sanchez et al., 2015).
Caenorhabditis elegans
It is one of the widely used models to study neurodegeneration for more than a decade.
Pros are the availability of genetic resources of this tiny transparent animal where all
302 neurons are mapped for their interactions and their short generation time
(Nussbaum-Krammer & Morimoto, 2014). Genetic strains were constructed that
express toxic protein aggregates such as Aβ, α-synuclein, TDP43 and polyglutamine
repeats in either whole body or tissue specific manner. They not only form visible
aggregates but also show the behaviour phenotype such as paralysis. Number of genetic
and chemical screens was conducted to identify modulators that rescue the behavioural
phenotype. This led to identification of small molecules that cleared toxic protein
aggregates and were further validated in higher model systems (Narayan et al., 2014).
Successful genetic screens too have identified many genes such as LRRK2, the
reduction of its kinase activity rescued the dopaminergic deficit motor phenotype (Yao
et al., 2013). Various regulators of HSR have been tested in the worm model to treat
proteotoxicity. Its transparent tissue enables for high content imaging. More
importantly, they also show a typical ageing symptoms making them an ideal tool to
investigate the interplay of metabolism, ageing and neurodegeneration
comprehensively (Chung et al., 2008).
Cellular Models
1. Yeast
The budding yeast (Saccharomyces cerevisiae) is a simple yet powerful tool to study
the cellular pathophysiological mechanisms underlying the protein toxicity(Smith &
Snyder, 2006). It recapitulates the toxicity of protein aggregates as that of neurons. This
is because the fundamental cellular features and vital cellular pathways are
conserved(Khurana & Lindquist, 2010). For instance, the membrane-bound organelles
such as mitochondria, Golgi, lysosome, endoplasmic reticulum and so on exist in yeast.
More importantly, the unfolded protein response is conserved as that of the mammalian
cells. The major advantages of yeast are short doubling time, existence of genetic
sources, amenable to genetic manipulation and scalable to high throughput genetic and
chemical screens. Also, around 3500 genes are found to be homologues as that of
human cells (Botstein et al., 1997; Kachroo et al., 2015). Pioneering work by Susan
Lindquist and her colleagues have shown that yeast cells expressing aggregate prone
genes and their variants that have been identified in ND have been used to understand
their pathobiology (Outeiro & Lindquist, 2003). The ER-Golgi trafficking defect due
to α-synuclein overexpression leads to cellular toxicity was first noted in yeast and
further validated in mammalian cells (Cooper et al., 2006; Winslow et al., 2010).
Several studies including ours have identified novel peptidomimetics and small
molecule autophagy modulators that ameliorate ND related aggregate proteotoxicity
(Khurana & Lindquist, 2010; Rajasekhar et al., 2015; Sarkar et al., 2007b). Some of
the obvious limitation of the yeast model is that it cannot recapitulate the complexities
of neuronal network and multicellularity that is present at the organ level.
2. iPSC
iPSC technology enables researchers to generate human specific, disease relevant cell
type such as neurons directly from patient fibroblasts. The advancement of gene editing
techniques such as CRISPR-Cas9 has simplified genetic knock out/in studies in iPSC-
derived neurons to understand the pathogenesis of neurodegeneration. The potential of
this model system to shed light on basic disease pathology mechanisms is massive
(Narayan et al., 2014). iPSC lines for AD, PD, Niemann-Pick disease type C and ALS
disease have been generated for their biological investigations (Chung et al., 2013;
Kiskinis et al., 2014; Ryan et al., 2013). Consequently, genetic or small molecule
screens can be performed using iPSC. The current limitations are 1) hurdle in scaling
up for high throughput screening due to their relative slow propagation rates, 2)
extensive and time-consuming neuronal differentiation protocols. However, they can
be used to validate the data generated from nonhuman disease models. For example,
yeast screen yielded the NAB2 compound where it rescued the disease phenotype and
validated its disease modifying mechanisms in iPSC(Chung et al., 2013).
Current understanding on the mechanistic insights of aggrephagy
These and other model systems have contributed immensely to unravel molecular
aspects of the process of aggrephagy. And how aggrephagy is perturbed by various
protein aggregates is detailed below.
Substrate recognition
Protein aggregate (substrate) recognition by receptors/adaptors such as Alfy,
p62/SQSTM1, Optineurin and Cue5/Tollip, is one of the first steps of autophagy for its
clearance (Stolz et al., 2014). The selectivity of autophagic cargo depends on specific
receptors/adaptors that recognize it by degradation marks. Autophagic receptors bind
to the ubiquitinated substrates through their respective domains to capture the
aggregates. They also tether them to autophagic machinery like LC3 to enable
autophagosome formation around the aggregates. The brief description pertaining to
autophagic receptors are as follows:
Alfy: This multidomain scaffolding protein recognizes ubiquitinated protein aggregates
for their clearance. It contains following domains: 1) Pleckstrin homology (PH)-
BEACH domain that binds to p62, 2) FYVE domain for PI3P binding, and 3) WD40
repeats that interacts with Atg5. It colocalizes with ubiquitin positive p62 aggregates
(Isakson et al., 2013). It stabilizes the LC3 and p62 interaction and also recruits Atg5
for the formation of autophagosomes that facilitated huntingtin polyQ aggregate
clearance (Filimonenko et al., 2010).
p62/SQSTM1: p62 is the adaptor for aggrephagy (Pankiv et al., 2007), mitophagy
(Geisler et al., 2010), pexophagy (Kim et al., 2008b) and xenophagy (Bah & Vergne,
2017). It possesses several domains namely: 1) UBA domain that binds ubiquitin, 2)
PB1 domain for aggregation of cargoes, and 3) LC3 Interacting Region (LIR) motif for
LC3 binding (Lim & Yue, 2015). It also has nuclear localization signal (NLS) and
nuclear export signal (NES) for nucleocytoplasmic shuttling (Pankiv et al., 2007). p62
mutations have been linked to sporadic and familial ALS through impaired clearance
of TDP-43 and SOD1 (Fecto et al., 2011). Paget’s disease of bone patients with
mutations in p62 are predisposed to ALS, a disease that is characterized by p62 positive
inclusions in neurons. Mutant p62 contributes to pathogenesis through multitude of
mechanisms and one of them is via over activation of nuclear factor-κB (NF-κB)
signaling (Chamoux et al., 2013).
Optineurin: It binds to ubiquitinated proteins through its UBA and NF-kB Essential
Modulator (NEMO) domains (Kachaner et al., 2012). On its other end, it binds to LC3
through LIR motif. Genetic mutations of optineurin are also associated with ALS.
Optineurin mutation is associated with rare ALS mutations leading to TAR DNA-
binding protein 43 (TDP-43) inclusions (Ito et al., 2011).
Cue5: Cue5 is the recently identified yeast autophagy receptor that binds to ubiquitin
through its CUE domain and Atg8 via its AIM1 and AIM2 motifs (Lu et al., 2014). Its
mammalian homologue is Tollip which is essential for the huntingtin polyQ clearance.
Valosin-Containing Protein (VCP): It is a member of AAA+ family of ATPase and
is involved in the sorting of ubiquitinated cargoes through endolysosomal pathway.
VCP mutation is associated with Paget’s disease of bone and Fronto Temporal dementia
(FTD). Overexpression or knockdown of VCP in cells leads to appearance of
autophagosomes that are immature with accumulation of ubiquitin positive cargoes
(Ritz et al., 2011).
Autophagosome formation
mTOR complex 1 (TORC1) negatively regulates autophagy. Various stimuli in neurons
such as ATP, ER stress, and specific amino acids repress TORC1 to activate ULK
complex (ULK1, FIP200, ULK2, Atg101 and Atg13) (Mizushima, 2010).
Phosphorylation of ULK1 at its active site leads to subsequent phosphorylation of other
components of complex for initiating autophagy (Chan et al., 2009). Although ULK1
phosphorylation is primarily regulated by TORC1, it can be also independently
modulated by AMP-activated protein kinase (AMPK) (Khan & Kumar, 2012). Also,
ULK1 phosphorylation leads to the translocation of class III PI3 Kinase complex
(beclin1, Atg14, Vps15 and Vps34) to isolation membranes (also known as omegasome
formation at the ER) by phosphorylating one of its components, AMBRA (Di
Bartolomeo et al., 2010). Vps34 activity generates phosphatidylinositol-3-phosphate
(PI3P) to bind to its effectors such as WIPI1 (WD repeat domain phosphoinositide
interacting 1) and WIPI2 (WD repeat domain phosphoinositide interacting 2) (Jaber &
Zong, 2013). This is to catalyse the ubiquitination like reactions at the isolation
membrane that aid autophagosome formation. Atg5-Atg12-Atg16L complex is formed
on the isolation membrane in presence of Atg7 and Atg10. This Atg5-Atg12-Atg16L
catalyses the covalent attachment of phosphatidylethanolamine to LC3 that facilitates
the closure of autophagosome membranes (Ichimura et al., 2000). Atg9 aims to supply
membranes for the growing autophagosomes by shuttling from various sources such as
endoplasmic reticulum-mitochondria contact sites (Hamasaki et al., 2013), Golgi
(Geng & Klionsky, 2010) and plasma membrane (Ravikumar et al., 2010) to
autophagosome formation site. ER has been suggested as a membrane source for
autophagosomes formed at synapse but the main source is not yet clear (Maday &
Holzbaur, 2014).
In neurons, how autophagy induced is still an enigma. Conventionally, the key trigger
for autophagy is starvation that induces autophagy in numerous cell types(Kim et al.,
2008a). However, even 48 hours of starvation did not induce GFP-LC3 puncta in brain
but profoundly induced autophagy in the liver (Mizushima et al., 2004). On the other
hand, while caloric restriction induced autophagy in cortical, Purkinje and motor
neurons, nutrient starvation failed to induce autophagy in cultured hippocampal
neurons (Kaushik et al., 2011). These contradicting results may mirror the neuronal
specificity in inducing and regulating autophagy. Several studies have shed light about
“other” ways of modulating autophagy in the brain.
Recently, the neuronal activity such as acute stimuli can trigger autophagy. Upon high
frequency stimulation, the Atg8 puncta is increased at neuromuscular junctions
(presynapse) in D. melanogaster (Vanhauwaert et al., 2017). Although the molecular
players and its mechanism(s) are not yet elucidated, calcium signalling can be a key
player. During exocytosis driven by action potential, there is remarkable increase in
calcium levels at presynapse (Rizzoli, 2014). Calcium can either enhance or inhibit
autophagy depending on the context and calcium responsive proteins are abundant at
presynapse. It is noteworthy to mention that investigating calcium-mediated autophagy
at presynapse can shed light on the novel mechanistic aspect of neuronal autophagy.
Interestingly, the presynaptic resident proteins such as Endophilin A, Basoon,
Synaptojanin 1 regulate autophagy by interacting with autophagy related proteins
(Vijayan & Verstreken, 2017).
Regulation of protein synthesis by TORC1 is implicated in synaptic plasticity (Kovacs
et al., 2007). However, TORC1 mediated autophagy induction at presynapse has not
been studied extensively. Autophagy mediated degradation of GABA receptors and
AMPA receptors (that are involved in synaptic plasticity) at post-synapse induce long
term depression (Shehata et al., 2012).
In PD model, α-synuclein perturbs Rab1a mediated Atg9 translocation to isolation
membrane leading to impairment of omegasome formation (Cooper et al., 2006). Atg9
trafficking is also abnormal in vacuolar protein sorting-associated protein 35 (VPS35)
D620N mutation that results in autosomal dominant case of PD (Zhou et al., 2017).
VPS35 (component of retromer complex) recruits actin nucleation-promoting WASP
and Scar homolog (WASH) complex to endosomes. Mutation in VPS35 perturbs this
recruitment to cause the abnormal Atg9 trafficking to impair autophagy(Zavodszky et
al., 2014).The E122D Atg5 mutation has been identified in childhood ataxia(Kim et al.,
2016). This disease is characterized by loss of motor coordination and cerebellar
hypoplasia. This mutation decreases the affinity of Atg5 to Atg12 and reduces the
autophagosome biogenesis and its flux (Kim et al., 2016).
β-propeller protein-associated neurodegeneration (BPAN), the static encephalopathy of
childhood with neurodegeneration in adulthood (SENDA) is caused by de novo
mutations in WDR45(Haack et al., 2013). WDR45 gene encodes WIPI4, the key
protein that bridges PI3P production and LC3 lipidation for autophagosome maturation
(Zhao et al., 2015). Neuronal specific knockout of WDR45 recapitulates some BPAN
disease phenotype such as impaired motor coordination, cognitive deficit, axonal
swelling with accumulation of ubiquitin positive aggregates (Saitsu et al., 2013).
Hexanucleotide repeats in C9ORF72 gene is one of the most common causes of ALS.
Different mechanisms have been proposed for this disease pathogenesis and
perturbation of autophagy is one of them. C9ORF72 interacts with ULK1 and affects
the phagophore initiation complex(Webster et al., 2016). In addition, C9ORF72 is a
part of WD repeat domain 41 (WDR41) and Smith-Magenis syndrome chromosome
region, candidate 8 (SMCR8) complex that is involved in both vesicular trafficking and
autophagy. This complex is a guanosine diphosphate (GDP)/guanosine triphosphate
(GTP) exchange factor (GEF) that activates the small GTPases Rab39 and Rab8 for
autophagosome formation (Amick & Ferguson, 2017).
Wild type huntingtin protein acts as a scaffold for autophagosome formation whereas
its mutant fails to recognize the cargo leading to “empty” autophagosomes(Martinez-
Vicente et al., 2010). It also impairs autophagosome transport and further accumulation
of autophagic substrates(Wong & Holzbaur, 2014). Mutant huntingtin interacts with
Rhes that are selectively expressed in striatum to inactivate it. Rhes interacts with beclin
1 to induce autophagy by reducing the bcl2-beclin 1 interaction (Subramaniam et al.,
2009). Furthermore, mTOR, is also sequestered in HD and spino-cerebellar ataxia 7
(SCA7) aggregates (Jimenez-Sanchez et al., 2012).
Autophagosome-lysosome fusion
Autophagosomes fuse with lysosomes to generate autolysosomes that digest the toxic
protein aggregates. In neurons, autophagosomes generated in axons are transported to
the lysosomes that are abundant near perinuclear MicroTubule-Organizing Centre
(MTOC). Microtubules and motor proteins such as dynein-dynactin complex are
involved in retrograde transport of autophagosomes towards neuronal cell body.
Mutations in dynein (axonal Charcot-Marie-Tooth hereditary neuropathy type 2) and
dynactin (motor neuron disease) motor protein complexes are implicated in
neurodegeneration pathogenesis indicating the importance of retrograde transport of
autophagosomes to fuse with lysosomes (Ferrucci et al., 2011). Interestingly, decreased
dynein activity resulted in the accumulation of autophagosomes, autolysosomes and
p62 positive inclusions in motor neurons before the onset of symptoms where they
degenerate upon clinical manifestations (Sasaki, 2011).
Amphisome formation (a fusion product of endosomes with autophagosome) is
perturbed in familial ALS and FTD and is associated with loss-of-function mutations
in CHMP2B (charged multivesicular body protein 2B). Mutant CHMP2B neurons
accumulate ubiquitin positive inclusion by disrupting ESCRT machinery
activity(Skibinski et al., 2005). Autophagy and endolysosomal pathways have
significant crosstalk pertaining to usage of cellular protein machineries. Mutations in
an endolysosomal pathway affects autophagy and vice versa (Otomo et al., 2011).
Endosomal maturation protein Rab7 is essential for autophagic flux and its mutation is
associated with bone related osteopetrosis (lysosomal perturbation) and
neurodegenerative CMT2 (autophagy flux perturbation) diseases (Tabata et al., 2010).
Furthermore, Rab7 significantly influences lysosome positioning. ALS2 protein
mutation, an activator of Rab5 perturbs ALS2 mediated Rab5 activation that hampers
amphisome formation as observed in familial cases of ALS (Otomo et al., 2011). The
coordinated crosstalk of endolysosomal and autophagy pathways to clear toxic protein
aggregates in healthy cells goes awry in neurodegeneration.
In neuronal specific interferon-β knockout of transgenic mouse model, the
autophagosome-lysosome fusion is affected with concomitant accumulation of
ubiquitin positive inclusion in neurons that leads to motor coordination and behavioural
impairments (Ejlerskov et al., 2015).
Regulation of lysosomal activity
Autophagosomes fuse with lysosomes for the clearance of its contents. For this process
to be efficient, the uncompromised lysosomal activity is essential. The lysosomal pH is
optimally (~4.5 to 5) maintained by proton pump vacuolar ATPase for the activity of
hydrolytic enzymes (proteases, peptidases, lipases and nucleases). Ionic balances of
lysosomes are regulated by presence of numerous ion channels (calcium, chloride and
potassium). Lysosomal associated membrane protein-1 (LAMP1) and LAMP2 prevents
the self-digestion of lysosomes (Nixon, 2013). The functional integrity of lysosomes is
compromised in most neurodegenerative disorders (Kroemer & Jaattela, 2005).
Lysosomes serve as key players in the initial stage of autophagy induction. Upon
perceiving the autophagy inducing stimuli, the TORC1 localized on the lysosomal
membrane is repressed and that further allows activation of transcription factor EB
(TFEB) to translocate to the nucleus. TFEB activates genes involved in lysosomal
biogenesis and autophagy process. TORC1 regulation of TFEB is achieved through
Rag-GTPase pathway (Kim et al., 2008a). TORC1 and TFEB activities are tightly
controlled by the presence of intracellular and lysosomal amino acid contents. If amino
acids are limiting inside the cells, for instance as in starvation, the TORC1 activity is
repressed and is followed by translocation of dephosphorylated TFEB to nucleus
resulting in upregulation of autophagy. On the other hand, the surplus amino acids lead
to reactivation of TORC1 to terminate the autophagy induction (Avruch et al., 2009).
The androgen receptor polyQ repeat mutant (implicated in SBMA) interacts with TFEB
and suppresses autophagy at transcription level (Cortes et al., 2014). SCA3 transgenic
animals show low levels of sirtuin 1 (deacetylates numerous autophagy and its related
proteins), parkin and beclin 1(Cunha-Santos et al., 2016).
Zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3) is repressor of
autophagy and has opposite function that of TFEB. Inhibition of mTOR enhances its
accumulation in the cytosol. Down regulating ZKSCAN3 induces autophagosome and
lysosomal biogenesis (Chauhan et al., 2013). Apart from this, around 20 different
transcription factors are reported to regulate the autophagy at gene transcription level
depending on the context of stimuli. For instance, p53, forkhead box O3 (FOXO3) and
microphthalmia-associated transcription factor (MITF), all profoundly affect
autophagy gene expression (Li et al., 2017).
Lysosomal storage disorders (LSDs) illustrates the nexus between lysosomal
dysfunction and neurodegeneration. In LSDs, the unavailability of functional lysosomal
hydrolytic enzymes leads to defective autophagy that manifests disease pathology in
brain. In Niemann Pick type C (NPC) disease, the mutations of NPC1 and/or NPC2
genes lead to defective cholesterol trafficking where profound autophagic vacuole are
observed in neurons (Elrick et al., 2012). In neuronal ceroid lipofuscinosis, the mutation
in CLN3 gene reduces autolysosome formation, whereas in Cathepsin D mutation that
causes the same disease where declined lysosomal proteolysis is observed (Nixon,
2004).
Therapeutic strategies for ND
Current therapeutic interventions for neurodegeneration include three different
strategies. First, preventing the toxic protein aggregate build-up. For instance, the
antisense oligonucleotides ameliorated the amyotrophic lateral sclerosis disease
phenotype under preclinical settings and showed significant safety in phase I clinical
trial (Nizzardo et al., 2016). Second, dissolving the already culminated toxic protein
aggregates inside the neurons. Various groups identified small molecules and peptides
that can bring about disintegration of the aggregate. This has been a widely used
strategy for many years as a promising anti-neurodegeneration therapeutic. For AD,
few small molecule candidates that dissolve the amyloid plaques are currently in the
clinical trials in USA and Europe. The third and recent approach is to promote cellular
pathways to capture and degrade the protein aggregates by either ubiquitin proteasome
(UPS) or autophagy systems. Numerous groups have demonstrated that
neurodegeneration could be ameliorated by upregulating the activities of cellular
clearance systems such as proteasome or autophagy through small molecules or
peptides. Many small molecule screens have been reported that have identified the
druggable candidate(s) (target proteins or pathways). For e.g., Rilmenidine, an
autophagy inducer is currently in clinical trial as a HD therapeutic in Europe.
Chemical modulation of autophagy
As mentioned earlier that upregulation of autophagy gene expression enhances the
longevity of several model organisms (Pyo et al., 2013). Convincing evidences
demonstrate that dysfunctional autophagy contribute to the pathogenesis of
neurodegeneration (Nixon, 2013). Importantly, autophagy can clear the toxic misfolded
protein aggregates. Mechanisms that govern degradation of toxic misfolded protein
aggregates is thus a therapeutically attractive target (Sarkar et al., 2007b). Numerous
studies demonstrated that pharmacological upregulation of autophagy to clear protein
aggregates is beneficial in ameliorating neurodegeneration.
mTOR dependent autophagy modulators
mTOR dependent modulators induce autophagy by repressing mTOR and it can be of
ATP competitive (e.g., Torin1) or non-ATP competitive (e.g., rapamycin). mTOR can
be found in two complexes such as TORC1 (negative regulator of autophagy) and
TORC2 (positive regulator of autophagy). Rapamycin and their analogues are relatively
safer owing to its non-ATP competitive mode of inhibition. The allosteric TORC1
inhibitor, rapamycin was the first identified small molecule autophagy inducer.
Rapamycin interacts with FK506-binding protein 12 (FKBP12) to inhibit the TORC1
activity(Lorenz & Heitman, 1995). Rapamycin has been demonstrated to be
neuroprotective in various diseases such as PD, HD, AD and FTD in an autophagy
dependent manner(Jahrling & Laberge, 2015). Limited absorption of rapamycin led to
the development of its analogues (rapalogs) such as everolimus, temsirolimus, and
ridaforolimus. Rapalogs are under rigorous investigation for their therapeutic potential
in neurodegeneration. For instance, Food and Drug Administration (FDA) approved
everolimus as a tuberous sclerosis therapeutic(Bissler et al., 2017). Torin1 inhibits both
TORC1 and TORC2 in concentration dependent manner (Ma et al., 2013). There are
classes of modulators that indirectly inhibit mTOR activity. For instance, metformin
(Type II diabetes therapeutic) inhibits mTOR through regulating AMPK pathway.
Another AMPK activator, Nilotinib also exerts neuroprotection by inhibiting mTOR
activity and is currently under phase II clinical trial for PD therapy (Karuppagounder
et al., 2014). PI103 belong to dual mTOR/class III PI3Kinase modulators that inhibit
both mTOR and AKT pathway to induce autophagy. However, due to its rapid in vivo
metabolism, PI103 is currently unsuitable for neurodegeneration therapy (Hassan et al.,
2013).
mTOR independent autophagy modulators
mTOR independent autophagy modulators are those that induce autophagy without
repressing the mTOR activity. mTOR being the epicentre for cellular growth signalling
whose chronic inhibition exerts significant toxicity. These inhibitors are preferred
therapeutically as significant side effects such as impaired wound healing and
immunosuppression that are classically associated with mTOR inhibitors can be
avoided. Thus, these are also more suited for long-term drug administration. Small
molecule screening for FDA approved drugs revealed that several modulators
ameliorated neurodegeneration pathogenesis in various model systems in mTOR
independent manner. This study revealed the involvement of two cyclical pathways
namely Gsα/calpain/Ca2+ (Cardenas et al., 2010) and EPAC/cAMP/PLCε/Ins(1,4,5)P3
(Williams et al., 2008) that are important for the mTOR independent clearance of
aggregates.
Rilmenidine, the imidazoline receptor inhibitor, enhances autophagy by reducing
cAMP levels. It has been shown to ameliorate neurodegeneration in various model
systems such as primary neurons and transgenic mouse models of HD. It is important
to note that rilmenidine is currently undergoing safety trials for HD in Europe (Williams
et al., 2008).
Other drugs identified to regulate autophagy through the cyclical pathway are lithium,
valproic acid and carbamazepine. Carbamazepine and valproic acid repress inositol
synthesis, while lithium inhibits inositol monophosphatase to reduce Ins(1,4,5)P3
levels and thus induce autophagy (Williams et al., 2008).
Modulators of Gsα/calpain/Ca2+pathway such as verapamil and amiodarone along with
calpain inhibitors such as calpeptin and calpastatin have shown to exert neuroprotective
potential by degrading the protein aggregates through an autophagy-mediated
mechanism (Williams et al., 2008).
Trehalose clears α-synuclein and mutant huntingtin protein aggregates in autophagy
dependent manner in various model systems (Sarkar et al., 2007a). It has been shown
to be neuroprotective in tauopathy models as well (Schaeffer et al., 2012). It extends
life span, curbs motor and cognitive deficits in transgenic HD and ALS mouse models
(Tanaka et al., 2004).
Perspectives
The etiological components, as well as the molecular and cellular points of convergence
in ND, remain elusive and hence optimizing a defined therapeutic approach has been
challenging. Cellular mechanisms that directly impact synaptic function, including
autophagy, endosomal trafficking, and mitochondrial homeostasis, are likely to
constitute effective interventional targets in therapy in future. It is becoming
increasingly evident from recent literature that clearing protein aggregates via protein
quality control systems such as aggrephagy hold therapeutic promise for curbing
neurodegenerative diseases.
Acknowledgments
We thank members of the autophagy lab (JNCASR), Mridhula Giridharan and Aparna
Hebbar for critical reading of the manuscript. We apologize to researchers whose work
could not be included due to constraint in space. We acknowledge Wellcome
Trust/DBT India Alliance Intermediate Fellowship (500159-Z-09-Z), DST-SERB grant
(EMR/2015/001946) and LSRB-DRDO grant (LSRB-31012017-2018) to RM, DST-
SERB grant (EMR/2015/001946) to JC, and JNCASR intramural funds.
Competing financial interests
All the authors declare no competing interests.
References
Akopian G., J. Barry, C. Cepeda and M. S. Levine 2016 Altered membrane properties
and firing patterns of external globus pallidus neurons in the R6/2 mouse model
of Huntington's disease. J Neurosci Res. 94, 1400-1410.
Amick J. and S. M. Ferguson 2017 C9orf72: At the intersection of lysosome cell
biology and neurodegenerative disease. Traffic. 18, 267-276.
Anckar J. and L. Sistonen 2011 Regulation of HSF1 function in the heat stress
response: implications in aging and disease. Annu Rev Biochem. 80, 1089-115.
Andre V. M., C. Cepeda and M. S. Levine 2010 Dopamine and glutamate in
Huntington's disease: A balancing act. CNS Neurosci Ther. 16, 163-78.
Andreassen O. A., A. Dedeoglu, P. Klivenyi, M. F. Beal and A. I. Bush 2000 N-acetyl-
L-cysteine improves survival and preserves motor performance in an animal
model of familial amyotrophic lateral sclerosis. Neuroreport. 11, 2491-3.
Arbuthnott G. W., C. A. Ingham and J. R. Wickens 2000 Dopamine and synaptic
plasticity in the neostriatum. J Anat. 196 ( Pt 4), 587-96.
Avruch J., X. Long, S. Ortiz-Vega, J. Rapley, A. Papageorgiou and N. Dai 2009
Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab. 296,
E592-602.
Bah A. and I. Vergne 2017 Macrophage Autophagy and Bacterial Infections. Front
Immunol. 8, 1483.
Balch W. E., R. I. Morimoto, A. Dillin and J. W. Kelly 2008 Adapting proteostasis
for disease intervention. Science. 319, 916-9.
Bhide P. G., M. Day, E. Sapp, C. Schwarz, A. Sheth, J. Kim. et al. 1996 Expression
of normal and mutant huntingtin in the developing brain. J Neurosci. 16, 5523-
35.
Bissler J. J., J. C. Kingswood, E. Radzikowska, B. A. Zonnenberg, E. Belousova, M.
D. Frost. et al. 2017 Everolimus long-term use in patients with tuberous
sclerosis complex: Four-year update of the EXIST-2 study. PLoS One. 12,
e0180939.
Blesa J., I. Trigo-Damas, M. Dileone, N. L. Del Rey, L. F. Hernandez and J. A. Obeso
2017 Compensatory mechanisms in Parkinson's disease: Circuits adaptations
and role in disease modification. Exp Neurol. 298, 148-161.
Bliss T. V. and G. L. Collingridge 1993 A synaptic model of memory: long-term
potentiation in the hippocampus. Nature. 361, 31-9.
Botstein D., S. A. Chervitz and J. M. Cherry 1997 Yeast as a model organism. Science.
277, 1259-60.
Branchi I., Z. Bichler, J. Berger-Sweeney and L. Ricceri 2003 Animal models of
mental retardation: from gene to cognitive function. Neurosci Biobehav Rev. 27,
141-53.
Brooks K. J., M. D. Hill, P. D. Hockings and D. G. Reid 2004 MRI detects early
hindlimb muscle atrophy in Gly93Ala superoxide dismutase-1 (G93A SOD1)
transgenic mice, an animal model of familial amyotrophic lateral sclerosis.
NMR Biomed. 17, 28-32.
Brose N., V. O'Connor and P. Skehel 2010 Synaptopathy: dysfunction of synaptic
function? Biochem Soc Trans. 38, 443-4.
Brown R. H., Jr. and W. Robberecht 2001 Amyotrophic lateral sclerosis: pathogenesis.
Semin Neurol. 21, 131-9.
Calabresi P., D. Centonze, P. Gubellini, G. A. Marfia, A. Pisani, G. Sancesario. et al.
2000 Synaptic transmission in the striatum: from plasticity to
neurodegeneration. Prog Neurobiol. 61, 231-65.
Calabresi P., R. Maj, A. Pisani, N. B. Mercuri and G. Bernardi 1992a Long-term
synaptic depression in the striatum: physiological and pharmacological
characterization. J Neurosci. 12, 4224-33.
Calabresi P., N. B. Mercuri, G. Sancesario and G. Bernardi 1993 Electrophysiology
of dopamine-denervated striatal neurons. Implications for Parkinson's disease.
Brain. 116 ( Pt 2), 433-52.
Calabresi P., A. Pisani, N. B. Mercuri and G. Bernardi 1992b Long-term Potentiation
in the Striatum is Unmasked by Removing the Voltage-dependent Magnesium
Block of NMDA Receptor Channels. Eur J Neurosci. 4, 929-935.
Calautti C., M. Naccarato, P. S. Jones, N. Sharma, D. D. Day, A. T. Carpenter. et al.
2007 The relationship between motor deficit and hemisphere activation balance
after stroke: A 3T fMRI study. Neuroimage. 34, 322-31.
Cardenas C., R. A. Miller, I. Smith, T. Bui, J. Molgo, M. Muller. et al. 2010 Essential
regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to
mitochondria. Cell. 142, 270-83.
Carriedo S. G., S. L. Sensi, H. Z. Yin and J. H. Weiss 2000 AMPA exposures induce
mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in
vitro. J Neurosci. 20, 240-50.
Centonze D., N. Battista, S. Rossi, N. B. Mercuri, A. Finazzi-Agro, G. Bernardi. et al.
2004 A critical interaction between dopamine D2 receptors and
endocannabinoids mediates the effects of cocaine on striatal gabaergic
Transmission. Neuropsychopharmacology. 29, 1488-97.
Cepeda C., M. A. Ariano, C. R. Calvert, J. Flores-Hernandez, S. H. Chandler, B. R.
Leavitt. et al. 2001 NMDA receptor function in mouse models of Huntington
disease. J Neurosci Res. 66, 525-39.
Cepeda C., D. M. Cummings, V. M. Andre, S. M. Holley and M. S. Levine 2010
Genetic mouse models of Huntington's disease: focus on electrophysiological
mechanisms. ASN Neuro. 2, e00033.
Cepeda C., N. Wu, V. M. Andre, D. M. Cummings and M. S. Levine 2007 The
corticostriatal pathway in Huntington's disease. Prog Neurobiol. 81, 253-71.
Chamoux E., S. McManus, G. Laberge, M. Bisson and S. Roux 2013 Involvement of
kinase PKC-zeta in the p62/p62(P392L)-driven activation of NF-kappaB in
human osteoclasts. Biochim Biophys Acta. 1832, 475-84.
Chan E. Y., A. Longatti, N. C. McKnight and S. A. Tooze 2009 Kinase-inactivated
ULK proteins inhibit autophagy via their conserved C-terminal domains using
an Atg13-independent mechanism. Mol Cell Biol. 29, 157-71.
Chang S., S. M. Bray, Z. Li, D. C. Zarnescu, C. He, P. Jin. et al. 2008 Identification
of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat
Chem Biol. 4, 256-63.
Chauhan S., J. G. Goodwin, S. Chauhan, G. Manyam, J. Wang, A. M. Kamat. et al.
2013 ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell.
50, 16-28.
Chung C. Y., V. Khurana, P. K. Auluck, D. F. Tardiff, J. R. Mazzulli, F. Soldner. et al.
2013 Identification and rescue of alpha-synuclein toxicity in Parkinson patient-
derived neurons. Science. 342, 983-7.
Chung K., M. M. Crane and H. Lu 2008 Automated on-chip rapid microscopy,
phenotyping and sorting of C. elegans. Nat Methods. 5, 637-43.
Citri A. and R. C. Malenka 2008 Synaptic plasticity: multiple forms, functions, and
mechanisms. Neuropsychopharmacology. 33, 18-41.
Cleveland D. W. and J. D. Rothstein 2001 From Charcot to Lou Gehrig: deciphering
selective motor neuron death in ALS. Nat Rev Neurosci. 2, 806-19.
Cooper A. A., A. D. Gitler, A. Cashikar, C. M. Haynes, K. J. Hill, B. Bhullar. et al.
2006 Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in
Parkinson's models. Science. 313, 324-8.
Cortes C. J., S. C. Ling, L. T. Guo, G. Hung, T. Tsunemi, L. Ly. et al. 2014 Muscle
expression of mutant androgen receptor accounts for systemic and motor neuron
disease phenotypes in spinal and bulbar muscular atrophy. Neuron. 82, 295-307.
Crawley J. N. 2008 Behavioral phenotyping strategies for mutant mice. Neuron. 57,
809-18.
Cummings D. M., C. Cepeda and M. S. Levine 2010 Alterations in striatal synaptic
transmission are consistent across genetic mouse models of Huntington's
disease. ASN Neuro. 2, e00036.
Cunha-Santos J., J. Duarte-Neves, V. Carmona, L. Guarente, L. Pereira de Almeida and
C. Cavadas 2016 Caloric restriction blocks neuropathology and motor deficits
in Machado-Joseph disease mouse models through SIRT1 pathway. Nat
Commun. 7, 11445.
De Duve C. and R. Wattiaux 1966 Functions of lysosomes. Annu Rev Physiol. 28,
435-92.
De Strooper B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert. et
al. 1998 Deficiency of presenilin-1 inhibits the normal cleavage of amyloid
precursor protein. Nature. 391, 387-90.
Di Bartolomeo S., M. Corazzari, F. Nazio, S. Oliverio, G. Lisi, M. Antonioli. et al.
2010 The dynamic interaction of AMBRA1 with the dynein motor complex
regulates mammalian autophagy. J Cell Biol. 191, 155-68.
DiFiglia M. 1997 Clinical Genetics, II. Huntington's disease: from the gene to
pathophysiology. Am J Psychiatry. 154, 1046.
Dihanich S. and C. Manzoni 2011 LRRK2: a problem lurking in vesicle trafficking?
J Neurosci. 31, 9787-8.
Ejlerskov P., J. G. Hultberg, J. Wang, R. Carlsson, M. Ambjorn, M. Kuss. et al. 2015
Lack of Neuronal IFN-beta-IFNAR Causes Lewy Body- and Parkinson's
Disease-like Dementia. Cell. 163, 324-39.
Elrick M. J., T. Yu, C. Chung and A. P. Lieberman 2012 Impaired proteolysis
underlies autophagic dysfunction in Niemann-Pick type C disease. Hum Mol
Genet. 21, 4876-87.
Fecto F., J. Yan, S. P. Vemula, E. Liu, Y. Yang, W. Chen. et al. 2011 SQSTM1
mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol.
68, 1440-6.
Feldmeyer D., K. Kask, R. Brusa, H. C. Kornau, R. Kolhekar, A. Rozov. et al. 1999
Neurological dysfunctions in mice expressing different levels of the Q/R site-
unedited AMPAR subunit GluR-B. Nat Neurosci. 2, 57-64.
Ferrucci M., F. Fulceri, L. Toti, P. Soldani, G. Siciliano, A. Paparelli. et al. 2011
Protein clearing pathways in ALS. Arch Ital Biol. 149, 121-49.
Filimonenko M., P. Isakson, K. D. Finley, M. Anderson, H. Jeong, T. J. Melia. et al.
2010 The selective macroautophagic degradation of aggregated proteins
requires the PI3P-binding protein Alfy. Mol Cell. 38, 265-79.
Fischer L. R. and J. D. Glass 2010 Oxidative stress induced by loss of Cu,Zn-
superoxide dismutase (SOD1) or superoxide-generating herbicides causes
axonal degeneration in mouse DRG cultures. Acta Neuropathol. 119, 249-59.
Fitzjohn S. M., R. A. Morton, F. Kuenzi, T. W. Rosahl, M. Shearman, H. Lewis. et al.
2001 Age-related impairment of synaptic transmission but normal long-term
potentiation in transgenic mice that overexpress the human APP695SWE
mutant form of amyloid precursor protein. J Neurosci. 21, 4691-8.
Fonnum F., J. Storm-Mathisen and I. Divac 1981 Biochemical evidence for glutamate
as neurotransmitter in corticostriatal and corticothalamic fibres in rat brain.
Neuroscience. 6, 863-73.
Gardoni F., B. Picconi, V. Ghiglieri, F. Polli, V. Bagetta, G. Bernardi. et al. 2006 A
critical interaction between NR2B and MAGUK in L-DOPA induced
dyskinesia. J Neurosci. 26, 2914-22.
Geisler S., K. M. Holmstrom, D. Skujat, F. C. Fiesel, O. C. Rothfuss, P. J. Kahle. et al.
2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and
p62/SQSTM1. Nat Cell Biol. 12, 119-31.
Geng J. and D. J. Klionsky 2010 The Golgi as a potential membrane source for
autophagy. Autophagy. 6, 950-1.
Goldberg A. L. 2003 Protein degradation and protection against misfolded or damaged
proteins. Nature. 426, 895-9.
Gonatas N. K., W. Anderson and I. Evangelista 1967 The contribution of altered
synapses in the senile plaque: an electron microscopic study in Alzheimer's
dementia. J Neuropathol Exp Neurol. 26, 25-39.
Graham R. K., M. A. Pouladi, P. Joshi, G. Lu, Y. Deng, N. P. Wu. et al. 2009
Differential susceptibility to excitotoxic stress in YAC128 mouse models of
Huntington disease between initiation and progression of disease. J Neurosci.
29, 2193-204.
Greengard P., A. C. Nairn, J. A. Girault, C. C. Ouimet, G. L. Snyder, G. Fisone. et al.
1998 The DARPP-32/protein phosphatase-1 cascade: a model for signal
integration. Brain Res Brain Res Rev. 26, 274-84.
Haack T. B., P. Hogarth, A. Gregory, H. Prokisch and S. J. Hayflick 2013 BPAN: the
only X-linked dominant NBIA disorder. Int Rev Neurobiol. 110, 85-90.
Hadano S., C. K. Hand, H. Osuga, Y. Yanagisawa, A. Otomo, R. S. Devon. et al. 2001
A gene encoding a putative GTPase regulator is mutated in familial
amyotrophic lateral sclerosis 2. Nat Genet. 29, 166-73.
Hamasaki M., N. Furuta, A. Matsuda, A. Nezu, A. Yamamoto, N. Fujita. et al. 2013
Autophagosomes form at ER-mitochondria contact sites. Nature. 495, 389-93.
Hardingham G. E., Y. Fukunaga and H. Bading 2002 Extrasynaptic NMDARs oppose
synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat
Neurosci. 5, 405-14.
Harnett M. M., M. A. Pineda, P. Latre de Late, R. J. Eason, S. Besteiro, W. Harnett. et
al. 2017 From Christian de Duve to Yoshinori Ohsumi: More to autophagy
than just dining at home. Biomed J. 40, 9-22.
Harper P. S. 1996 New genes for old diseases: the molecular basis of myotonic
dystrophy and Huntington's disease. The Lumleian Lecture 1995. J R Coll
Physicians Lond. 30, 221-31.
Hassan B., A. Akcakanat, A. M. Holder and F. Meric-Bernstam 2013 Targeting the
PI3-kinase/Akt/mTOR signaling pathway. Surg Oncol Clin N Am. 22, 641-64.
Heath P. R. and P. J. Shaw 2002 Update on the glutamatergic neurotransmitter system
and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve. 26,
438-58.
Herrera-Marschitz M., C. F. Loidl, Z. B. You, K. Andersson, R. Silveira, W. T.
O'Connor. et al. 1994 Neurocircuitry of the basal ganglia studied by
monitoring neurotransmitter release. Effects of intracerebral and perinatal
asphyctic lesions. Mol Neurobiol. 9, 171-82.
Hetz C. 2012 The unfolded protein response: controlling cell fate decisions under ER
stress and beyond. Nat Rev Mol Cell Biol. 13, 89-102.
Hetz C. and B. Mollereau 2014 Disturbance of endoplasmic reticulum proteostasis in
neurodegenerative diseases. Nat Rev Neurosci. 15, 233-49.
Higgins G. A. and H. Jacobsen 2003 Transgenic mouse models of Alzheimer's disease:
phenotype and application. Behav Pharmacol. 14, 419-38.
Hsia A. Y., E. Masliah, L. McConlogue, G. Q. Yu, G. Tatsuno, K. Hu. et al. 1999
Plaque-independent disruption of neural circuits in Alzheimer's disease mouse
models. Proc Natl Acad Sci U S A. 96, 3228-33.
Hyttinen J. M., M. Amadio, J. Viiri, A. Pascale, A. Salminen and K. Kaarniranta 2014
Clearance of misfolded and aggregated proteins by aggrephagy and
implications for aggregation diseases. Ageing Res Rev. 18, 16-28.
Ichimura Y., T. Kirisako, T. Takao, Y. Satomi, Y. Shimonishi, N. Ishihara. et al. 2000
A ubiquitin-like system mediates protein lipidation. Nature. 408, 488-92.
Isakson P., P. Holland and A. Simonsen 2013 The role of ALFY in selective autophagy.
Cell Death Differ. 20, 12-20.
Ito H., M. Nakamura, O. Komure, T. Ayaki, R. Wate, H. Maruyama. et al. 2011
Clinicopathologic study on an ALS family with a heterozygous E478G
optineurin mutation. Acta Neuropathol. 122, 223-9.
Jaber N. and W. X. Zong 2013 Class III PI3K Vps34: essential roles in autophagy,
endocytosis, and heart and liver function. Ann N Y Acad Sci. 1280, 48-51.
Jahrling J. B. and R. M. Laberge 2015 Age-Related Neurodegeneration Prevention
Through mTOR Inhibition: Potential Mechanisms and Remaining Questions.
Curr Top Med Chem. 15, 2139-51.
Jimenez-Sanchez M., W. Lam, M. Hannus, B. Sonnichsen, S. Imarisio, A. Fleming. et
al. 2015 siRNA screen identifies QPCT as a druggable target for Huntington's
disease. Nat Chem Biol. 11, 347-354.
Jimenez-Sanchez M., F. Thomson, E. Zavodszky and D. C. Rubinsztein 2012
Autophagy and polyglutamine diseases. Prog Neurobiol. 97, 67-82.
Jones A. L., J. D. Wood and P. S. Harper 1997 Huntington disease: advances in
molecular and cell biology. J Inherit Metab Dis. 20, 125-38.
Joshi P. R., N. P. Wu, V. M. Andre, D. M. Cummings, C. Cepeda, J. A. Joyce. et al.
2009 Age-dependent alterations of corticostriatal activity in the YAC128
mouse model of Huntington disease. J Neurosci. 29, 2414-27.
Julien J. P. 2001 Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.
Cell. 104, 581-91.
Kachaner D., P. Genin, E. Laplantine and R. Weil 2012 Toward an integrative view
of Optineurin functions. Cell Cycle. 11, 2808-18.
Kachroo A. H., J. M. Laurent, C. M. Yellman, A. G. Meyer, C. O. Wilke and E. M.
Marcotte 2015 Evolution. Systematic humanization of yeast genes reveals
conserved functions and genetic modularity. Science. 348, 921-5.
Kambe Y., N. Nakamichi, T. Takarada, R. Fukumori, R. Nakazato, E. Hinoi. et al. 2011
A possible pivotal role of mitochondrial free calcium in neurotoxicity mediated
by N-methyl-d-aspartate receptors in cultured rat hippocampal neurons.
Neurochem Int. 59, 10-20.
Kampinga H. H. and E. A. Craig 2010 The HSP70 chaperone machinery: J proteins
as drivers of functional specificity. Nat Rev Mol Cell Biol. 11, 579-92.
Kanning K. C., A. Kaplan and C. E. Henderson 2010 Motor neuron diversity in
development and disease. Annu Rev Neurosci. 33, 409-40.
Karuppagounder S. S., S. Brahmachari, Y. Lee, V. L. Dawson, T. M. Dawson and H.
S. Ko 2014 The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a
preclinical animal model of Parkinson's disease. Sci Rep. 4, 4874.
Kaushik S., J. A. Rodriguez-Navarro, E. Arias, R. Kiffin, S. Sahu, G. J. Schwartz. et al.
2011 Autophagy in hypothalamic AgRP neurons regulates food intake and
energy balance. Cell Metab. 14, 173-83.
Khan S. H. and R. Kumar 2012 Role of an intrinsically disordered conformation in
AMPK-mediated phosphorylation of ULK1 and regulation of autophagy. Mol
Biosyst. 8, 91-6.
Khedraki A., E. J. Reed, S. H. Romer, Q. Wang, W. Romine, M. M. Rich. et al. 2017
Depressed Synaptic Transmission and Reduced Vesicle Release Sites in
Huntington's Disease Neuromuscular Junctions. J Neurosci. 37, 8077-8091.
Khurana V. and S. Lindquist 2010 Modelling neurodegeneration in Saccharomyces
cerevisiae: why cook with baker's yeast? Nat Rev Neurosci. 11, 436-49.
Kim E., P. Goraksha-Hicks, L. Li, T. P. Neufeld and K. L. Guan 2008a Regulation of
TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 10, 935-45.
Kim M., E. Sandford, D. Gatica, Y. Qiu, X. Liu, Y. Zheng. et al. 2016 Mutation in
ATG5 reduces autophagy and leads to ataxia with developmental delay. Elife.
5.
Kim P. K., D. W. Hailey, R. T. Mullen and J. Lippincott-Schwartz 2008b Ubiquitin
signals autophagic degradation of cytosolic proteins and peroxisomes. Proc
Natl Acad Sci U S A. 105, 20567-74.
Kirkin V., D. G. McEwan, I. Novak and I. Dikic 2009 A role for ubiquitin in selective
autophagy. Mol Cell. 34, 259-69.
Kiskinis E., J. Sandoe, L. A. Williams, G. L. Boulting, R. Moccia, B. J. Wainger. et al.
2014 Pathways disrupted in human ALS motor neurons identified through
genetic correction of mutant SOD1. Cell Stem Cell. 14, 781-95.
Klapstein G. J., R. S. Fisher, H. Zanjani, C. Cepeda, E. S. Jokel, M. F. Chesselet. et al.
2001 Electrophysiological and morphological changes in striatal spiny neurons
in R6/2 Huntington's disease transgenic mice. J Neurophysiol. 86, 2667-77.
Kolodziejczyk K. and L. A. Raymond 2016 Differential changes in thalamic and
cortical excitatory synapses onto striatal spiny projection neurons in a
Huntington disease mouse model. Neurobiol Dis. 86, 62-74.
Kostic V., V. Jackson-Lewis, F. de Bilbao, M. Dubois-Dauphin and S. Przedborski
1997 Bcl-2: prolonging life in a transgenic mouse model of familial
amyotrophic lateral sclerosis. Science. 277, 559-62.
Kovacs K. A., P. Steullet, M. Steinmann, K. Q. Do, P. J. Magistretti, O. Halfon. et al.
2007 TORC1 is a calcium- and cAMP-sensitive coincidence detector involved
in hippocampal long-term synaptic plasticity. Proc Natl Acad Sci U S A. 104,
4700-5.
Kroemer G. and M. Jaattela 2005 Lysosomes and autophagy in cell death control. Nat
Rev Cancer. 5, 886-97.
Kumar D. R., F. Aslinia, S. H. Yale and J. J. Mazza 2011 Jean-Martin Charcot: the
father of neurology. Clin Med Res. 9, 46-9.
Kuner R., A. J. Groom, I. Bresink, H. C. Kornau, V. Stefovska, G. Muller. et al. 2005
Late-onset motoneuron disease caused by a functionally modified AMPA
receptor subunit. Proc Natl Acad Sci U S A. 102, 5826-31.
Labbadia J. and R. I. Morimoto 2015 Repression of the Heat Shock Response Is a
Programmed Event at the Onset of Reproduction. Mol Cell. 59, 639-50.
LaFerla F. M. and K. N. Green 2012 Animal models of Alzheimer disease. Cold Spring
Harb Perspect Med. 2.
Lepeta K., M. V. Lourenco, B. C. Schweitzer, P. V. Martino Adami, P. Banerjee, S.
Catuara-Solarz. et al. 2016 Synaptopathies: synaptic dysfunction in
neurological disorders - A review from students to students. J Neurochem. 138,
785-805.
Levine M. S., C. Cepeda, M. A. Hickey, S. M. Fleming and M. F. Chesselet 2004
Genetic mouse models of Huntington's and Parkinson's diseases: illuminating
but imperfect. Trends Neurosci. 27, 691-7.
Levine M. S., G. J. Klapstein, A. Koppel, E. Gruen, C. Cepeda, M. E. Vargas. et al.
1999 Enhanced sensitivity to N-methyl-D-aspartate receptor activation in
transgenic and knockin mouse models of Huntington's disease. J Neurosci Res.
58, 515-32.
Li L., R. Zviti, C. Ha, Z. V. Wang, J. A. Hill and F. Lin 2017 Forkhead box O3
(FoxO3) regulates kidney tubular autophagy following urinary tract obstruction.
J Biol Chem. 292, 13774-13783.
Li X. J. 1999 The early cellular pathology of Huntington's disease. Mol Neurobiol. 20,
111-24.
Lim J. and Z. Yue 2015 Neuronal aggregates: formation, clearance, and spreading.
Dev Cell. 32, 491-501.
Lipton S. A. and P. A. Rosenberg 1994 Excitatory amino acids as a final common
pathway for neurologic disorders. N Engl J Med. 330, 613-22.
Lorenz M. C. and J. Heitman 1995 TOR mutations confer rapamycin resistance by
preventing interaction with FKBP12-rapamycin. J Biol Chem. 270, 27531-7.
Lovinger D. M., E. C. Tyler and A. Merritt 1993 Short- and long-term synaptic
depression in rat neostriatum. J Neurophysiol. 70, 1937-49.
Lu K., I. Psakhye and S. Jentsch 2014 Autophagic clearance of polyQ proteins
mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family.
Cell. 158, 549-63.
Luheshi L. M., G. G. Tartaglia, A. C. Brorsson, A. P. Pawar, I. E. Watson, F. Chiti. et
al. 2007 Systematic in vivo analysis of the intrinsic determinants of amyloid
Beta pathogenicity. PLoS Biol. 5, e290.
Lundblad M., B. Picconi, H. Lindgren and M. A. Cenci 2004 A model of L-DOPA-
induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and
cellular parameters of nigrostriatal function. Neurobiol Dis. 16, 110-23.
Ma N., Q. Liu, L. Zhang, E. P. Henske and Y. Ma 2013 TORC1 signaling is governed
by two negative regulators in fission yeast. Genetics. 195, 457-68.
Maday S. and E. L. Holzbaur 2014 Autophagosome biogenesis in primary neurons
follows an ordered and spatially regulated pathway. Dev Cell. 30, 71-85.
Mangiarini L., K. Sathasivam, M. Seller, B. Cozens, A. Harper, C. Hetherington. et al.
1996 Exon 1 of the HD gene with an expanded CAG repeat is sufficient to
cause a progressive neurological phenotype in transgenic mice. Cell. 87, 493-
506.
Martinez-Vicente M., Z. Talloczy, E. Wong, G. Tang, H. Koga, S. Kaushik. et al. 2010
Cargo recognition failure is responsible for inefficient autophagy in
Huntington's disease. Nat Neurosci. 13, 567-76.
Martire A., R. Pepponi, M. R. Domenici, A. Ferrante, V. Chiodi and P. Popoli 2013
BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the
effects are genotype specific and adenosine A2A receptor is involved. J
Neurochem. 125, 225-35.
Masliah E., R. D. Terry, R. M. DeTeresa and L. A. Hansen 1989
Immunohistochemical quantification of the synapse-related protein
synaptophysin in Alzheimer disease. Neurosci Lett. 103, 234-9.
McGeer P. L., E. G. McGeer, U. Scherer and K. Singh 1977 A glutamatergic
corticostriatal path? Brain Res. 128, 369-73.
Menalled L. and D. Brunner 2014 Animal models of Huntington's disease for
translation to the clinic: best practices. Mov Disord. 29, 1375-90.
Menalled L. B. and M. F. Chesselet 2002 Mouse models of Huntington's disease.
Trends Pharmacol Sci. 23, 32-9.
Mhyre T. R., J. T. Boyd, R. W. Hamill and K. A. Maguire-Zeiss 2012 Parkinson's
disease. Subcell Biochem. 65, 389-455.
Miller B. R., A. G. Walker, A. S. Shah, S. J. Barton and G. V. Rebec 2008
Dysregulated information processing by medium spiny neurons in striatum of
freely behaving mouse models of Huntington's disease. J Neurophysiol. 100,
2205-16.
Milnerwood A. J., D. M. Cummings, G. M. Dallerac, J. Y. Brown, S. C. Vatsavayai,
M. C. Hirst. et al. 2006 Early development of aberrant synaptic plasticity in a
mouse model of Huntington's disease. Hum Mol Genet. 15, 1690-703.
Milnerwood A. J., C. M. Gladding, M. A. Pouladi, A. M. Kaufman, R. M. Hines, J. D.
Boyd. et al. 2010 Early increase in extrasynaptic NMDA receptor signaling
and expression contributes to phenotype onset in Huntington's disease mice.
Neuron. 65, 178-90.
Milnerwood A. J. and L. A. Raymond 2007 Corticostriatal synaptic function in mouse
models of Huntington's disease: early effects of huntingtin repeat length and
protein load. J Physiol. 585, 817-31.
Milnerwood A. J. and L. A. Raymond 2010 Early synaptic pathophysiology in
neurodegeneration: insights from Huntington's disease. Trends Neurosci. 33,
513-23.
Mizushima N. 2010 The role of the Atg1/ULK1 complex in autophagy regulation.
Curr Opin Cell Biol. 22, 132-9.
Mizushima N., A. Yamamoto, M. Matsui, T. Yoshimori and Y. Ohsumi 2004 In vivo
analysis of autophagy in response to nutrient starvation using transgenic mice
expressing a fluorescent autophagosome marker. Mol Biol Cell. 15, 1101-11.
Murer M. G., K. Y. Tseng, F. Kasanetz, M. Belluscio and L. A. Riquelme 2002 Brain
oscillations, medium spiny neurons, and dopamine. Cell Mol Neurobiol. 22,
611-32.
Mymrikov E. V., M. Daake, B. Richter, M. Haslbeck and J. Buchner 2017 The
Chaperone Activity and Substrate Spectrum of Human Small Heat Shock
Proteins. J Biol Chem. 292, 672-684.
Narayan P., S. Ehsani and S. Lindquist 2014 Combating neurodegenerative disease
with chemical probes and model systems. Nat Chem Biol. 10, 911-20.
Nasir J., S. B. Floresco, J. R. O'Kusky, V. M. Diewert, J. M. Richman, J. Zeisler. et al.
1995 Targeted disruption of the Huntington's disease gene results in embryonic
lethality and behavioral and morphological changes in heterozygotes. Cell. 81,
811-23.
Nicholls D. G., L. Johnson-Cadwell, S. Vesce, M. Jekabsons and N. Yadava 2007
Bioenergetics of mitochondria in cultured neurons and their role in glutamate
excitotoxicity. J Neurosci Res. 85, 3206-12.
Nistico R., M. Pignatelli, S. Piccinin, N. B. Mercuri and G. Collingridge 2012
Targeting synaptic dysfunction in Alzheimer's disease therapy. Mol Neurobiol.
46, 572-87.
Nitsch C. and R. Riesenberg 1995 Synaptic reorganisation in the rat striatum after
dopaminergic deafferentation: an ultrastructural study using glutamate
decarboxylase immunocytochemistry. Synapse. 19, 247-63.
Nixon R. A. 2004 Niemann-Pick Type C disease and Alzheimer's disease: the APP-
endosome connection fattens up. Am J Pathol. 164, 757-61.
Nixon R. A. 2013 The role of autophagy in neurodegenerative disease. Nat Med. 19,
983-97.
Nizzardo M., C. Simone, F. Rizzo, G. Ulzi, A. Ramirez, M. Rizzuti. et al. 2016
Morpholino-mediated SOD1 reduction ameliorates an amyotrophic lateral
sclerosis disease phenotype. Sci Rep. 6, 21301.
Nussbaum-Krammer C. I. and R. I. Morimoto 2014 Caenorhabditis elegans as a model
system for studying non-cell-autonomous mechanisms in protein-misfolding
diseases. Dis Model Mech. 7, 31-9.
Otomo A., R. Kunita, K. Suzuki-Utsunomiya, J. E. Ikeda and S. Hadano 2011
Defective relocalization of ALS2/alsin missense mutants to Rac1-induced
macropinosomes accounts for loss of their cellular function and leads to
disturbed amphisome formation. FEBS Lett. 585, 730-6.
Outeiro T. F. and S. Lindquist 2003 Yeast cells provide insight into alpha-synuclein
biology and pathobiology. Science. 302, 1772-5.
Pankiv S., T. H. Clausen, T. Lamark, A. Brech, J. A. Bruun, H. Outzen. et al. 2007
p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of
ubiquitinated protein aggregates by autophagy. J Biol Chem. 282, 24131-45.
Pardo C. A., Z. Xu, D. R. Borchelt, D. L. Price, S. S. Sisodia and D. W. Cleveland
1995 Superoxide dismutase is an abundant component in cell bodies, dendrites,
and axons of motor neurons and in a subset of other neurons. Proc Natl Acad
Sci U S A. 92, 954-8.
Paulsen J. S., D. R. Langbehn, J. C. Stout, E. Aylward, C. A. Ross, M. Nance. et al.
2008 Detection of Huntington's disease decades before diagnosis: the Predict-
HD study. J Neurol Neurosurg Psychiatry. 79, 874-80.
Pehar M., M. R. Vargas, P. Cassina, A. G. Barbeito, J. S. Beckman and L. Barbeito
2005 Complexity of astrocyte-motor neuron interactions in amyotrophic lateral
sclerosis. Neurodegener Dis. 2, 139-46.
Peng T. I., M. J. Jou, S. S. Sheu and J. T. Greenamyre 1998 Visualization of NMDA
receptor-induced mitochondrial calcium accumulation in striatal neurons. Exp
Neurol. 149, 1-12.
Pouladi M. A., R. K. Graham, J. M. Karasinska, Y. Xie, R. D. Santos, A. Petersen. et
al. 2009 Prevention of depressive behaviour in the YAC128 mouse model of
Huntington disease by mutation at residue 586 of huntingtin. Brain. 132, 919-
32.
Powers E. T., R. I. Morimoto, A. Dillin, J. W. Kelly and W. E. Balch 2009 Biological
and chemical approaches to diseases of proteostasis deficiency. Annu Rev
Biochem. 78, 959-91.
Pozueta J., R. Lefort and M. L. Shelanski 2013 Synaptic changes in Alzheimer's
disease and its models. Neuroscience. 251, 51-65.
Puzzo D., R. Piacentini, M. Fa, W. Gulisano, D. D. Li Puma, A. Staniszewski. et al.
2017 LTP and memory impairment caused by extracellular Abeta and Tau
oligomers is APP-dependent. Elife. 6.
Pyo J. O., S. M. Yoo, H. H. Ahn, J. Nah, S. H. Hong, T. I. Kam. et al. 2013
Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat
Commun. 4, 2300.
Rajasekhar K., S. N. Suresh, R. Manjithaya and T. Govindaraju 2015 Rationally
designed peptidomimetic modulators of abeta toxicity in Alzheimer's disease.
Sci Rep. 5, 8139.
Ravikumar B., K. Moreau, L. Jahreiss, C. Puri and D. C. Rubinsztein 2010 Plasma
membrane contributes to the formation of pre-autophagosomal structures. Nat
Cell Biol. 12, 747-57.
Raychaudhuri S., C. Loew, R. Korner, S. Pinkert, M. Theis, M. Hayer-Hartl. et al. 2014
Interplay of acetyltransferase EP300 and the proteasome system in regulating
heat shock transcription factor 1. Cell. 156, 975-85.
Ritz D., M. Vuk, P. Kirchner, M. Bug, S. Schutz, A. Hayer. et al. 2011 Endolysosomal
sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and
impaired by VCP disease mutations. Nat Cell Biol. 13, 1116-23.
Rizzoli S. O. 2014 Synaptic vesicle recycling: steps and principles. EMBO J. 33, 788-
822.
Rosen D. R. 1993 Mutations in Cu/Zn superoxide dismutase gene are associated with
familial amyotrophic lateral sclerosis. Nature. 364, 362.
Rouse S. T., M. J. Marino, S. R. Bradley, H. Awad, M. Wittmann and P. J. Conn 2000
Distribution and roles of metabotropic glutamate receptors in the basal ganglia
motor circuit: implications for treatment of Parkinson's disease and related
disorders. Pharmacol Ther. 88, 427-35.
Rowan M. J., I. Klyubin, W. K. Cullen and R. Anwyl 2003 Synaptic plasticity in
animal models of early Alzheimer's disease. Philos Trans R Soc Lond B Biol
Sci. 358, 821-8.
Ryan S. D., N. Dolatabadi, S. F. Chan, X. Zhang, M. W. Akhtar, J. Parker. et al. 2013
Isogenic human iPSC Parkinson's model shows nitrosative stress-induced
dysfunction in MEF2-PGC1alpha transcription. Cell. 155, 1351-64.
Saitsu H., T. Nishimura, K. Muramatsu, H. Kodera, S. Kumada, K. Sugai. et al. 2013
De novo mutations in the autophagy gene WDR45 cause static encephalopathy
of childhood with neurodegeneration in adulthood. Nat Genet. 45, 445-9, 449e1.
Sanelli T., W. Ge, C. Leystra-Lantz and M. J. Strong 2007 Calcium mediated
excitotoxicity in neurofilament aggregate-bearing neurons in vitro is NMDA
receptor dependant. J Neurol Sci. 256, 39-51.
Sarkar S., J. E. Davies, Z. Huang, A. Tunnacliffe and D. C. Rubinsztein 2007a
Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the
clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 282, 5641-52.
Sarkar S., E. O. Perlstein, S. Imarisio, S. Pineau, A. Cordenier, R. L. Maglathlin. et al.
2007b Small molecules enhance autophagy and reduce toxicity in Huntington's
disease models. Nat Chem Biol. 3, 331-8.
Sasaguri H., P. Nilsson, S. Hashimoto, K. Nagata, T. Saito, B. De Strooper. et al. 2017
APP mouse models for Alzheimer's disease preclinical studies. EMBO J. 36,
2473-2487.
Sasaki S. 2011 Autophagy in spinal cord motor neurons in sporadic amyotrophic
lateral sclerosis. J Neuropathol Exp Neurol. 70, 349-59.
Sasaki S. and S. Maruyama 1994 Decreased synaptophysin immunoreactivity of the
anterior horns in motor neuron disease. Acta Neuropathol. 87, 125-8.
Schaeffer V., I. Lavenir, S. Ozcelik, M. Tolnay, D. T. Winkler and M. Goedert 2012
Stimulation of autophagy reduces neurodegeneration in a mouse model of
human tauopathy. Brain. 135, 2169-77.
Scheff S. W. and D. A. Price 1993 Synapse loss in the temporal lobe in Alzheimer's
disease. Ann Neurol. 33, 190-9.
Schwarcz R., W. O. Whetsell, Jr. and R. M. Mangano 1983 Quinolinic acid: an
endogenous metabolite that produces axon-sparing lesions in rat brain. Science.
219, 316-8.
Selkoe D. J. 2002 Alzheimer's disease is a synaptic failure. Science. 298, 789-91.
Sepers M. D. and L. A. Raymond 2014 Mechanisms of synaptic dysfunction and
excitotoxicity in Huntington's disease. Drug Discov Today. 19, 990-6.
Shehata M., H. Matsumura, R. Okubo-Suzuki, N. Ohkawa and K. Inokuchi 2012
Neuronal stimulation induces autophagy in hippocampal neurons that is
involved in AMPA receptor degradation after chemical long-term depression. J
Neurosci. 32, 10413-22.
Sheng M. and C. Sala 2001 PDZ domains and the organization of supramolecular
complexes. Annu Rev Neurosci. 24, 1-29.
Skibinski G., N. J. Parkinson, J. M. Brown, L. Chakrabarti, S. L. Lloyd, H. Hummerich.
et al. 2005 Mutations in the endosomal ESCRTIII-complex subunit CHMP2B
in frontotemporal dementia. Nat Genet. 37, 806-8.
Slow E. J., J. van Raamsdonk, D. Rogers, S. H. Coleman, R. K. Graham, Y. Deng. et
al. 2003 Selective striatal neuronal loss in a YAC128 mouse model of
Huntington disease. Hum Mol Genet. 12, 1555-67.
Smith M. G. and M. Snyder 2006 Yeast as a model for human disease. Curr Protoc
Hum Genet. Chapter 15, Unit 15 6.
Sontag E. M., R. S. Samant and J. Frydman 2017 Mechanisms and Functions of Spatial
Protein Quality Control. Annu Rev Biochem. 86, 97-122.
Spillantini M. G., M. L. Schmidt, V. M. Lee, J. Q. Trojanowski, R. Jakes and M.
Goedert 1997 Alpha-synuclein in Lewy bodies. Nature. 388, 839-40.
Spires-Jones T. and S. Knafo 2012 Spines, plasticity, and cognition in Alzheimer's
model mice. Neural Plast. 2012, 319836.
Stolz A., A. Ernst and I. Dikic 2014 Cargo recognition and trafficking in selective
autophagy. Nat Cell Biol. 16, 495-501.
Subramaniam S., K. M. Sixt, R. Barrow and S. H. Snyder 2009 Rhes, a striatal specific
protein, mediates mutant-huntingtin cytotoxicity. Science. 324, 1327-30.
Sun G. Z., Y. C. He, X. K. Ma, S. T. Li, D. J. Chen, M. Gao. et al. 2017 Hippocampal
synaptic and neural network deficits in young mice carrying the human APOE4
gene. CNS Neurosci Ther. 23, 748-758.
Tabata K., K. Matsunaga, A. Sakane, T. Sasaki, T. Noda and T. Yoshimori 2010
Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway
via a novel Rab7-binding domain. Mol Biol Cell. 21, 4162-72.
Tanaka M., Y. Machida, S. Niu, T. Ikeda, N. R. Jana, H. Doi. et al. 2004 Trehalose
alleviates polyglutamine-mediated pathology in a mouse model of Huntington
disease. Nat Med. 10, 148-54.
Terry R. D., E. Masliah, D. P. Salmon, N. Butters, R. DeTeresa, R. Hill. et al. 1991
Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is
the major correlate of cognitive impairment. Ann Neurol. 30, 572-80.
Trancikova A., D. Ramonet and D. J. Moore 2011 Genetic mouse models of
neurodegenerative diseases. Prog Mol Biol Transl Sci. 100, 419-82.
Van Damme P., M. Dewil, W. Robberecht and L. Van Den Bosch 2005 Excitotoxicity
and amyotrophic lateral sclerosis. Neurodegener Dis. 2, 147-59.
van der Staay F. J., S. S. Arndt and R. E. Nordquist 2009 Evaluation of animal models
of neurobehavioral disorders. Behav Brain Funct. 5, 11.
Vanhauwaert R., S. Kuenen, R. Masius, A. Bademosi, J. Manetsberger, N. Schoovaerts.
et al. 2017 The SAC1 domain in synaptojanin is required for autophagosome
maturation at presynaptic terminals. EMBO J. 36, 1392-1411.
Vergara R., C. Rick, S. Hernandez-Lopez, J. A. Laville, J. N. Guzman, E. Galarraga. et
al. 2003 Spontaneous voltage oscillations in striatal projection neurons in a rat
corticostriatal slice. J Physiol. 553, 169-82.
Vijayan V. and P. Verstreken 2017 Autophagy in the presynaptic compartment in
health and disease. J Cell Biol. 216, 1895-1906.
Vogels O. J., W. J. Oyen, B. G. van Engelen, G. W. Padberg and M. W. Horstink 1999
Decreased striatal dopamine-receptor binding in sporadic ALS: glutamate
hyperactivity? Neurology. 52, 1275-7.
Vogels O. J., J. Veltman, W. J. Oyen and M. W. Horstink 2000 Decreased striatal
dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and
multiple system atrophy (MSA): D2 receptor down-regulation versus striatal
cell degeneration. J Neurol Sci. 180, 62-5.
von Lewinski F. and B. U. Keller 2005 Ca2+, mitochondria and selective motoneuron
vulnerability: implications for ALS. Trends Neurosci. 28, 494-500.
Vonsattel J. P., R. H. Myers, T. J. Stevens, R. J. Ferrante, E. D. Bird and E. P.
Richardson, Jr. 1985 Neuropathological classification of Huntington's disease.
J Neuropathol Exp Neurol. 44, 559-77.
Walker F. O. 2007 Huntington's disease. Lancet. 369, 218-28.
Walther D. M., P. Kasturi, M. Zheng, S. Pinkert, G. Vecchi, P. Ciryam. et al. 2017
Widespread Proteome Remodeling and Aggregation in Aging C. elegans. Cell.
168, 944.
Wang F., L. A. Durfee and J. M. Huibregtse 2013 A cotranslational ubiquitination
pathway for quality control of misfolded proteins. Mol Cell. 50, 368-78.
Wang G., X. Liu, M. A. Gaertig, S. Li and X. J. Li 2016 Ablation of huntingtin in
adult neurons is nondeleterious but its depletion in young mice causes acute
pancreatitis. Proc Natl Acad Sci U S A. 113, 3359-64.
Webster C. P., E. F. Smith, C. S. Bauer, A. Moller, G. M. Hautbergue, L. Ferraiuolo.
et al. 2016 The C9orf72 protein interacts with Rab1a and the ULK1 complex
to regulate initiation of autophagy. EMBO J. 35, 1656-76.
Williams A., S. Sarkar, P. Cuddon, E. K. Ttofi, S. Saiki, F. H. Siddiqi. et al. 2008
Novel targets for Huntington's disease in an mTOR-independent autophagy
pathway. Nat Chem Biol. 4, 295-305.
Winslow A. R., C. W. Chen, S. Corrochano, A. Acevedo-Arozena, D. E. Gordon, A. A.
Peden. et al. 2010 alpha-Synuclein impairs macroautophagy: implications for
Parkinson's disease. J Cell Biol. 190, 1023-37.
Wong Y. C. and E. L. Holzbaur 2014 The regulation of autophagosome dynamics by
huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading
to defective cargo degradation. J Neurosci. 34, 1293-305.
Yang Y., A. Hentati, H. X. Deng, O. Dabbagh, T. Sasaki, M. Hirano. et al. 2001 The
gene encoding alsin, a protein with three guanine-nucleotide exchange factor
domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat
Genet. 29, 160-5.
Yao C., W. M. Johnson, Y. Gao, W. Wang, J. Zhang, M. Deak. et al. 2013 Kinase
inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2
toxicity. Hum Mol Genet. 22, 328-44.
Zaffagnini G. and S. Martens 2016 Mechanisms of Selective Autophagy. J Mol Biol.
428, 1714-24.
Zavodszky E., M. N. Seaman, K. Moreau, M. Jimenez-Sanchez, S. Y. Breusegem, M.
E. Harbour. et al. 2014 Mutation in VPS35 associated with Parkinson's disease
impairs WASH complex association and inhibits autophagy. Nat Commun. 5,
3828.
Zhao Y. G., L. Sun, G. Miao, C. Ji, H. Zhao, H. Sun. et al. 2015 The autophagy gene
Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis.
Autophagy. 11, 881-90.
Zhou L., W. Wang, C. Hoppel, J. Liu and X. Zhu 2017 Parkinson's disease-associated
pathogenic VPS35 mutation causes complex I deficits. Biochim Biophys Acta.
1863, 2791-2795.
Zona C., A. Ferri, R. Gabbianelli, N. B. Mercuri, G. Bernardi, G. Rotilio. et al. 1998
Voltage-activated sodium currents in a cell line expressing a Cu,Zn superoxide
dismutase typical of familial ALS. Neuroreport. 9, 3515-8.
Received 21 December 2017; revised 9 March 2018; accepted 20 March 2018
Table 1: Summary of synaptic dysfunction observed in different
neurodegenerative diseases.
Properties Amyotrophic
Lateral Sclerosis
Parkinson`s
Disease
Alzheimer`
s Disease
Huntington
`s Disease
Basal Synaptic
Transmission
(BST)
Impaired
transmission (()
presynaptic relase)
(Maselli, Wollman
et al. 1993)
Unaltered in
Medium spiny
neurons
(MSN’s) of
LRRK2 over
expressing
mice
(Beccano-
Kelly, Volta et
al. 2015)
Altered
BST was
observed in
App695Swe
mutant,
Apoe4 mice
(), AppInd
mice ()
(Hsia,
Masliah et
al. 1999,
Fitzjohn,
Morton et
al. 2001,
Puzzo,
Piacentini
et al. 2017,
Sun, He et
al. 2017)
In R6/2,
BST is
altered ()
(Cepeda,
Ariano et al.
2001,
Klapstein,
Fisher et al.
2001,
Milnerwood
, Cummings
et al. 2006,
Khedraki,
Reed et al.
2017).
Neurotransmitt
er Release
Increase in
Glutamate-induced
excitotoxicity;
Presynaptic
transmission
deficit
(Coyle and
Schwarcz 1976,
Lipton and
Rosenberg 1994,
Doble 1999,
Kiernan, Vucic et
al. 2011)
Deficiency of
dopamine in
the
nigrostriatal
system, and in
levels of
somatostatin.
(Rinne, Rinne
et al. 1984)
SV trafficking
defects (Esposi
to, Ana Clara
et al. 2012)
Increased
activity of
GABA and 5-
HTT (Anden
1974,
Grabowska
and Michaluk
Increased
presynaptic
function
(Sun, He et
al. 2017)
In R6/2,
altered
presynaptic
release (),
Post Tetanic
Potentiation
(), and in
YAC128 in
12 months
()
(Murphy,
Carter et al.
2000,
Cepeda,
Ariano et al.
2001,
Klapstein,
Fisher et al.
2001,
Milnerwood,
Cummings
1974, Maj,
Pawlowski et
al. 1974,
Hollister,
Breese et al.
1976)
et al. 2006,
Andre,
Cepeda et al.
2011,
Khedraki,
Reed et al.
2017).
Synaptic
Plasticity
Impaired LTP in
Ubqln2P497H and
Sod1
mice (Geracitano,
Paolucci et al.
2003, Gorrie,
Fecto et al. 2014)
LTP observed
in original
LTD-inducing
stimulus.
(Kreitzer and
Malenka 2005,
Bagetta,
Ghiglieri et al.
2010)
LTP in
AAV-
App/Ps1
(), Apoe4
()
(Audrain,
Fol et al.
2016,
Puzzo,
Piacentini
et al. 2017,
Sun, He et
al. 2017).
Impaired
LTP and
LTD in
R6/2
(Murphy,
Carter et al.
2000).
Cell Intrinsic
Properties
Altered
excitability and
altered fast
afterhyperpolarizat
ion (fAHP) and
slow
afterhyperpolarizat
ion (sAHP) in
Sod1 (), Tardbp
(),
Ubqln2P497H(),
Sod1A4V () mice
(Fischer, Culver et
al. 2004, Murray,
Talbot et al. 2010,
Zhou, Huang et al.
2010, Wainger,
Kiskinis et al.
2014, Radzicki,
Liu et al. 2016,
Kim, Hughes et al.
2017)
Increased
postsynaptic
potentials,
Intrinsic
membrane
properties,
postsynaptic
responses to
different
agonists of
excitatory
amino acid
receptors not
altered in
neurons
recorded from
dopamine-
depleted slices
(Calabresi,
Mercuri et al.
1993)
Highly
disorganise
d synapses,
increased
and
dispersed
tonic
glutamaterg
ic current
amplitude
in AAV-
App/Ps1
(Audrain,
Fol et al.
2016).
Increased
NMDA /
AMPA
ratio (Hsia,
Masliah et
al. 1999).
Decreased
in the
frequency
of mEPSC
and no
change in
amplitude
Altered
input,
resting
membrane
potentials,
time
constants
and action
potentials in
CAG40 KI
(), R6/2
()and
YAC128
()
(Levine,
Klapstein et
al. 1999,
Klapstein,
Fisher et al.
2001,
Graham,
Pouladi et
al. 2009,
Cummings,
Cepeda et
al. 2010).
on
application
of
Amyloid-β
in culture
(Yu,
Polepalli et
al. 2012).
Regions
involved
Motor cortex upper and lower
motor neurons,
Brain stem and
Spinal cord
(Agosta, Chio et
al. 2010, Kumar,
Aslinia et al. 2011)
Substantia
nigra, Putamen
Caudate
nucleus,
Globus
pallidus and
Cerebral
cortex (Sian,
Dexter et al.
1994)
Initially
Entorhinal
Cortex,
Hippocamp
us and later
cerebral
cortex but
eventually
all regions
are
affected.
Prefrontal,
motor and
Striatum
(globus
pallidus and
the
substantia
nigra pars
reticulate).
HTT and
mutant HTT
(mHTT)
proteins
expressed
ubiquitously
,
predominant
ly in the
striatum
Receptors and
Neurotransmitt
ers involved
Acetylcholine
receptors
(AChRs) (Palma,
Reyes-Ruiz et al.
2016)
Glutamate
receptor (Paul and
de Belleroche
2014)
Loss of
metabotropic
glutamate
receptor-mediated
regulation
(Vermeiren,
Hemptinne et al.
2006)
Cholinergic-
muscarinic
receptors
GABA
receptor
(Rinne, Rinne
et al. 1984)
Overactivation
of glutamate
receptors
(Bergman,
Wichmann et
al. 1994,
Hassani,
Mouroux et al.
1996)
Nicotinic
and
muscarinic
acetylcholi
ne
receptors
(Kihara and
Shimohama
2004).
Cytokine
receptors
(Nagae,
Araki et al.
2016).
NMDA
receptor
and
Glutamate
(Danysz
and Parsons
2012).
Dopamine
(Martorana
NMDA
receptor
(Levine,
Klapstein et
al. 1999,
Paoletti,
Vila et al.
2008).
mGluR`s
( group
2,3),
AMPA,
Kainate,
Dopamine,
Muscarinic
and GABA
Receptors
(Cha,
Kosinski et
al. 1998,
Sepers and
Raymond
2014)
and Koch
2014).
Dopaminer
gic D1-like
receptors,
substance P
(SP) and
dynorphin
and D2-like
receptors
and met-
enkephalin
are
implicated
(Haber and
Nauta 1983,
Andre,
Cepeda et
al. 2010).
Impaired
Dopamine
and
Glutamate
Homeostasi
s (Andre,
Cepeda et
al. 2010).
Chromosome
/Genes
involved
21q22.1 SOD1
2q33-2q35 Alsin
9q34 SETX
15q15-21 SPG 11
16p11.2 FUS
20q13.3 VAPB
14q11.2 ANG
6q21 FIG 4
1p36.2 TARDBP
10p13 OPTN
9p13.3 VCP
Xp11 UBQLN2
9p21 C9ORF72
(Chen, Sayana et
al. 2013)
4q21 SNCA
12q12 LRRK2
6q25–q27
Parkin
1p35–p36
PINK1
1p36 DJ-1
1p36
ATP13A2
(Lesage and
Brice 2009)
APP
(21q21.3) (Yoshikai, Sasaki et al. 1990, Thinakaran and Koo 2008). PSEN1
(14q24.3)
(Esler and
Wolfe
2001).
PSEN2
(1q42.13)
(Steiner
2004).
4p16.3
chromosom
al fragment
containing
IT15 gene.
Summary of different synaptic function properties that were altered in
neurodegenerative diseases, mainly Alzherimer’s, Parkinson’s, Huntington’s and
Amyotrophic Lateral Sclerosis. () or () indicates decrease or increase in that
specific property in the said mouse model.
Agosta, F., A. Chio, M. Cosottini, N. De Stefano, A. Falini, M. Mascalchi, M. A. Rocca,
V. Silani, G. Tedeschi and M. Filippi (2010). "The present and the future of
neuroimaging in amyotrophic lateral sclerosis." AJNR Am J Neuroradiol 31(10): 1769-
1777.
Anden, N. E. (1974). "Inhibition of the turnover of the brain dopamine after treatment
with the gammaaminobutyrate: 2-oxyglutarate transaminase inhibitor aminooxyacetic
acid." Naunyn Schmiedebergs Arch Pharmacol 283(4): 419-424.
Andre, V. M., C. Cepeda, Y. E. Fisher, M. Huynh, N. Bardakjian, S. Singh, X. W. Yang
and M. S. Levine (2011). "Differential electrophysiological changes in striatal output
neurons in Huntington's disease." J Neurosci 31(4): 1170-1182.
Andre, V. M., C. Cepeda and M. S. Levine (2010). "Dopamine and glutamate in
Huntington's disease: A balancing act." CNS Neurosci Ther 16(3): 163-178.
Audrain, M., R. Fol, P. Dutar, B. Potier, J. M. Billard, J. Flament, S. Alves, M. A.
Burlot, G. Dufayet-Chaffaud, A. P. Bemelmans, J. Valette, P. Hantraye, N. Deglon, N.
Cartier and J. Braudeau (2016). "Alzheimer's disease-like APP processing in wild-type
mice identifies synaptic defects as initial steps of disease progression." Mol
Neurodegener 11: 5.
Bagetta, V., V. Ghiglieri, C. Sgobio, P. Calabresi and B. Picconi (2010). "Synaptic
dysfunction in Parkinson's disease." Biochem Soc Trans 38(2): 493-497.
Beccano-Kelly, D. A., M. Volta, L. N. Munsie, S. A. Paschall, I. Tatarnikov, K. Co, P.
Chou, L. P. Cao, S. Bergeron, E. Mitchell, H. Han, H. L. Melrose, L. Tapia, L. A.
Raymond, M. J. Farrer and A. J. Milnerwood (2015). "LRRK2 overexpression alters
glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal
transduction, motor activity and memory." Hum Mol Genet 24(5): 1336-1349.
Bergman, H., T. Wichmann, B. Karmon and M. R. DeLong (1994). "The primate
subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism." J
Neurophysiol 72(2): 507-520.
Calabresi, P., N. B. Mercuri, G. Sancesario and G. Bernardi (1993). "Electrophysiology
of dopamine-denervated striatal neurons. Implications for Parkinson's disease." Brain
116 ( Pt 2): 433-452.
Cepeda, C., M. A. Ariano, C. R. Calvert, J. Flores-Hernandez, S. H. Chandler, B. R.
Leavitt, M. R. Hayden and M. S. Levine (2001). "NMDA receptor function in mouse
models of Huntington disease." J Neurosci Res 66(4): 525-539.
Cha, J. H., C. M. Kosinski, J. A. Kerner, S. A. Alsdorf, L. Mangiarini, S. W. Davies, J.
B. Penney, G. P. Bates and A. B. Young (1998). "Altered brain neurotransmitter
receptors in transgenic mice expressing a portion of an abnormal human huntington
disease gene." Proc Natl Acad Sci U S A 95(11): 6480-6485.
Chen, S., P. Sayana, X. Zhang and W. Le (2013). "Genetics of amyotrophic lateral
sclerosis: an update." Mol Neurodegener 8: 28.
Coyle, J. T. and R. Schwarcz (1976). "Lesion of striatal neurones with kainic acid
provides a model for Huntington's chorea." Nature 263(5574): 244-246.
Cummings, D. M., C. Cepeda and M. S. Levine (2010). "Alterations in striatal synaptic
transmission are consistent across genetic mouse models of Huntington's disease." ASN
Neuro 2(3): e00036.
Danysz, W. and C. G. Parsons (2012). "Alzheimer's disease, beta-amyloid, glutamate,
NMDA receptors and memantine--searching for the connections." Br J Pharmacol
167(2): 324-352.
Doble, A. (1999). "The role of excitotoxicity in neurodegenerative disease: implications
for therapy." Pharmacol Ther 81(3): 163-221.
Esler, W. P. and M. S. Wolfe (2001). "A portrait of Alzheimer secretases--new features
and familiar faces." Science 293(5534): 1449-1454.
Esposito, G., F. Ana Clara and P. Verstreken (2012). "Synaptic vesicle trafficking and
Parkinson's disease." Dev Neurobiol 72(1): 134-144.
Fischer, L. R., D. G. Culver, P. Tennant, A. A. Davis, M. Wang, A. Castellano-Sanchez,
J. Khan, M. A. Polak and J. D. Glass (2004). "Amyotrophic lateral sclerosis is a distal
axonopathy: evidence in mice and man." Exp Neurol 185(2): 232-240.
Fitzjohn, S. M., R. A. Morton, F. Kuenzi, T. W. Rosahl, M. Shearman, H. Lewis, D.
Smith, D. S. Reynolds, C. H. Davies, G. L. Collingridge and G. R. Seabrook (2001).
"Age-related impairment of synaptic transmission but normal long-term potentiation in
transgenic mice that overexpress the human APP695SWE mutant form of amyloid
precursor protein." J Neurosci 21(13): 4691-4698.
Geracitano, R., E. Paolucci, S. Prisco, E. Guatteo, C. Zona, P. Longone, M. Ammassari-
Teule, G. Bernardi, N. Berretta and N. B. Mercuri (2003). "Altered long-term
corticostriatal synaptic plasticity in transgenic mice overexpressing human CU/ZN
superoxide dismutase (GLY(93)-->ALA) mutation." Neuroscience 118(2): 399-408.
Gorrie, G. H., F. Fecto, D. Radzicki, C. Weiss, Y. Shi, H. Dong, H. Zhai, R. Fu, E. Liu,
S. Li, H. Arrat, E. H. Bigio, J. F. Disterhoft, M. Martina, E. Mugnaini, T. Siddique and
H. X. Deng (2014). "Dendritic spinopathy in transgenic mice expressing
ALS/dementia-linked mutant UBQLN2." Proc Natl Acad Sci U S A 111(40): 14524-
14529.
Grabowska, M. and J. Michaluk (1974). "On the role of serotonin in apomorphine-
induced locomotor stimulation in rats." Pharmacol Biochem Behav 2(2): 263-266.
Graham, R. K., M. A. Pouladi, P. Joshi, G. Lu, Y. Deng, N. P. Wu, B. E. Figueroa, M.
Metzler, V. M. Andre, E. J. Slow, L. Raymond, R. Friedlander, M. S. Levine, B. R.
Leavitt and M. R. Hayden (2009). "Differential susceptibility to excitotoxic stress in
YAC128 mouse models of Huntington disease between initiation and progression of
disease." J Neurosci 29(7): 2193-2204.
Haber, S. N. and W. J. Nauta (1983). "Ramifications of the globus pallidus in the rat as
indicated by patterns of immunohistochemistry." Neuroscience 9(2): 245-260.
Hassani, O. K., M. Mouroux and J. Feger (1996). "Increased subthalamic neuronal
activity after nigral dopaminergic lesion independent of disinhibition via the globus
pallidus." Neuroscience 72(1): 105-115.
Hollister, A. S., G. R. Breese, C. M. Kuhn, B. R. Cooper and S. M. Schanberg (1976).
"An inhibitory role for brain serotonin-containing systems in the locomotor effects of
d-amphetamine." J Pharmacol Exp Ther 198(1): 12-22.
Hsia, A. Y., E. Masliah, L. McConlogue, G. Q. Yu, G. Tatsuno, K. Hu, D. Kholodenko,
R. C. Malenka, R. A. Nicoll and L. Mucke (1999). "Plaque-independent disruption of
neural circuits in Alzheimer's disease mouse models." Proc Natl Acad Sci U S A 96(6):
3228-3233.
Khedraki, A., E. J. Reed, S. H. Romer, Q. Wang, W. Romine, M. M. Rich, R. J.
Talmadge and A. A. Voss (2017). "Depressed Synaptic Transmission and Reduced
Vesicle Release Sites in Huntington's Disease Neuromuscular Junctions." J Neurosci
37(34): 8077-8091.
Kiernan, M. C., S. Vucic, B. C. Cheah, M. R. Turner, A. Eisen, O. Hardiman, J. R.
Burrell and M. C. Zoing (2011). "Amyotrophic lateral sclerosis." Lancet 377(9769):
942-955.
Kihara, T. and S. Shimohama (2004). "Alzheimer's disease and acetylcholine
receptors." Acta Neurobiol Exp (Wars) 64(1): 99-105.
Kim, J., E. G. Hughes, A. S. Shetty, P. Arlotta, L. A. Goff, D. E. Bergles and S. P.
Brown (2017). "Changes in the Excitability of Neocortical Neurons in a Mouse Model
of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are
Modulated by Advancing Disease." J Neurosci 37(37): 9037-9053.
Klapstein, G. J., R. S. Fisher, H. Zanjani, C. Cepeda, E. S. Jokel, M. F. Chesselet and
M. S. Levine (2001). "Electrophysiological and morphological changes in striatal spiny
neurons in R6/2 Huntington's disease transgenic mice." J Neurophysiol 86(6): 2667-
2677.
Kreitzer, A. C. and R. C. Malenka (2005). "Dopamine modulation of state-dependent
endocannabinoid release and long-term depression in the striatum." J Neurosci 25(45):
10537-10545.
Kumar, D. R., F. Aslinia, S. H. Yale and J. J. Mazza (2011). "Jean-Martin Charcot: the
father of neurology." Clin Med Res 9(1): 46-49.
Lesage, S. and A. Brice (2009). "Parkinson's disease: from monogenic forms to genetic
susceptibility factors." Hum Mol Genet 18(R1): R48-59.
Levine, M. S., G. J. Klapstein, A. Koppel, E. Gruen, C. Cepeda, M. E. Vargas, E. S.
Jokel, E. M. Carpenter, H. Zanjani, R. S. Hurst, A. Efstratiadis, S. Zeitlin and M. F.
Chesselet (1999). "Enhanced sensitivity to N-methyl-D-aspartate receptor activation in
transgenic and knockin mouse models of Huntington's disease." J Neurosci Res 58(4):
515-532.
Lipton, S. A. and P. A. Rosenberg (1994). "Excitatory amino acids as a final common
pathway for neurologic disorders." N Engl J Med 330(9): 613-622.
Maj, J., L. Pawlowski and J. Sarnek (1974). "The role of brain 5-hydroxytryptamine in
the central action of L-DOPA." Adv Biochem Psychopharmacol 10: 253-256.
Martorana, A. and G. Koch (2014). ""Is dopamine involved in Alzheimer's disease?"."
Front Aging Neurosci 6: 252.
Maselli, R. A., R. L. Wollman, C. Leung, B. Distad, S. Palombi, D. P. Richman, E. F.
Salazar-Grueso and R. P. Roos (1993). "Neuromuscular transmission in amyotrophic
lateral sclerosis." Muscle Nerve 16(11): 1193-1203.
Milnerwood, A. J., D. M. Cummings, G. M. Dallerac, J. Y. Brown, S. C. Vatsavayai,
M. C. Hirst, P. Rezaie and K. P. Murphy (2006). "Early development of aberrant
synaptic plasticity in a mouse model of Huntington's disease." Hum Mol Genet 15(10):
1690-1703.
Murphy, K. P., R. J. Carter, L. A. Lione, L. Mangiarini, A. Mahal, G. P. Bates, S. B.
Dunnett and A. J. Morton (2000). "Abnormal synaptic plasticity and impaired spatial
cognition in mice transgenic for exon 1 of the human Huntington's disease mutation."
J Neurosci 20(13): 5115-5123.
Murray, L. M., K. Talbot and T. H. Gillingwater (2010). "Review: neuromuscular
synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and
spinal muscular atrophy." Neuropathol Appl Neurobiol 36(2): 133-156.
Nagae, T., K. Araki, Y. Shimoda, L. I. Sue, T. G. Beach and Y. Konishi (2016).
"Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimer's
Disease." J Clin Cell Immunol 7(4).
Palma, E., J. M. Reyes-Ruiz, D. Lopergolo, C. Roseti, C. Bertollini, G. Ruffolo, P.
Cifelli, E. Onesti, C. Limatola, R. Miledi and M. Inghilleri (2016). "Acetylcholine
receptors from human muscle as pharmacological targets for ALS therapy." Proc Natl
Acad Sci U S A 113(11): 3060-3065.
Paoletti, P., I. Vila, M. Rife, J. M. Lizcano, J. Alberch and S. Gines (2008).
"Dopaminergic and glutamatergic signaling crosstalk in Huntington's disease
neurodegeneration: the role of p25/cyclin-dependent kinase 5." J Neurosci 28(40):
10090-10101.
Paul, P. and J. de Belleroche (2014). "The role of D-serine and glycine as co-agonists
of NMDA receptors in motor neuron degeneration and amyotrophic lateral sclerosis
(ALS)." Front Synaptic Neurosci 6: 10.
Puzzo, D., R. Piacentini, M. Fa, W. Gulisano, D. D. Li Puma, A. Staniszewski, H.
Zhang, M. R. Tropea, S. Cocco, A. Palmeri, P. Fraser, L. D'Adamio, C. Grassi and O.
Arancio (2017). "LTP and memory impairment caused by extracellular Abeta and Tau
oligomers is APP-dependent." Elife 6.
Radzicki, D., E. Liu, H. X. Deng, T. Siddique and M. Martina (2016). "Early
Impairment of Synaptic and Intrinsic Excitability in Mice Expressing ALS/Dementia-
Linked Mutant UBQLN2." Front Cell Neurosci 10: 216.
Rinne, U. K., J. O. Rinne, J. K. Rinne, K. Laakso and P. Lonnberg (1984). "Brain
neurotransmitters and neuropeptides in Parkinson's disease." Acta Physiol Pharmacol
Latinoam 34(3): 287-299.
Sepers, M. D. and L. A. Raymond (2014). "Mechanisms of synaptic dysfunction and
excitotoxicity in Huntington's disease." Drug Discov Today 19(7): 990-996.
Sian, J., D. T. Dexter, A. J. Lees, S. Daniel, Y. Agid, F. Javoy-Agid, P. Jenner and C.
D. Marsden (1994). "Alterations in glutathione levels in Parkinson's disease and other
neurodegenerative disorders affecting basal ganglia." Ann Neurol 36(3): 348-355.
Steiner, H. (2004). "Uncovering gamma-secretase." Curr Alzheimer Res 1(3): 175-181.
Sun, G. Z., Y. C. He, X. K. Ma, S. T. Li, D. J. Chen, M. Gao, S. F. Qiu, J. X. Yin, J.
Shi and J. Wu (2017). "Hippocampal synaptic and neural network deficits in young
mice carrying the human APOE4 gene." CNS Neurosci Ther 23(9): 748-758.
Thinakaran, G. and E. H. Koo (2008). "Amyloid precursor protein trafficking,
processing, and function." J Biol Chem 283(44): 29615-29619.
Vermeiren, C., I. Hemptinne, N. Vanhoutte, S. Tilleux, J. M. Maloteaux and E.
Hermans (2006). "Loss of metabotropic glutamate receptor-mediated regulation of
glutamate transport in chemically activated astrocytes in a rat model of amyotrophic
lateral sclerosis." J Neurochem 96(3): 719-731.
Wainger, B. J., E. Kiskinis, C. Mellin, O. Wiskow, S. S. Han, J. Sandoe, N. P. Perez,
L. A. Williams, S. Lee, G. Boulting, J. D. Berry, R. H. Brown, Jr., M. E. Cudkowicz,
B. P. Bean, K. Eggan and C. J. Woolf (2014). "Intrinsic membrane hyperexcitability of
amyotrophic lateral sclerosis patient-derived motor neurons." Cell Rep 7(1): 1-11.
Yoshikai, S., H. Sasaki, K. Doh-ura, H. Furuya and Y. Sakaki (1990). "Genomic
organization of the human amyloid beta-protein precursor gene." Gene 87(2): 257-263.
Yu, W., J. Polepalli, D. Wagh, J. Rajadas, R. Malenka and B. Lu (2012). "A critical
role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses
and dendritic spines." Hum Mol Genet 21(6): 1384-1390.
Zhou, H., C. Huang, H. Chen, D. Wang, C. P. Landel, P. Y. Xia, R. Bowser, Y. J. Liu
and X. G. Xia (2010). "Transgenic rat model of neurodegeneration caused by mutation
in the TDP gene." PLoS Genet 6(3): e1000887.
Figure 1. Formation of aggrephagosome. Aggregate proteins are ubiquitinated (Ub)
which are recognized by adaptor proteins. p62, NDP-52, NBR1 and optineurin are some
of the examples of adaptor proteins that have a ubiquitin binding domain and
additionally have LC3 Interacting Region (LIR) that can recruit LC3 and thereby
facilitate cargo recognition and capture.
Figure 2. Signalling pathways affected in neurodegenerative disorders. Schematic
to show impaired synaptic function due to altered function of different signalling
pathways in different neurodegenerative disorders. Presence of aggregates in these
diseases leads to an increase in presynaptic release of glutamate or dopamine upon
stimulation that activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor (AMPAR), dopamine receptor1 (D1R) and dopamine receptor2 (D2R)
respectively.
a) Activation of AMPARs leads to N-methyl-D-aspartate receptors (NMDAR)
activation which is followed by Ca2+ influx. Additionally, Voltage gated Ca2+ channel
(VGCC) further facilitates the Ca2+ influx, leading to an increased intracellular Ca2+
levels at the postsynapse. This increased levels of Ca2+ results in: 1) Excitotoxicity, 2)
Mitochondrial Dysfunction, 3) Reactive Oxygen Species (ROS) activation, 4)
CASPASE activation, 5) Apoptosis, and 6) mTOR activation (autophagy inhibition).
These events eventually result in neuronal dysfunction, neurodegeneration, and
cognitive impairments.
b) Stimulation of metabotropic glutamate receptor5 (mGluR5) by glutamate leads to
activation of inositol 1,4,5-trisphosphate (IP3). In neurodegeneration, the aggregates
strongly bind to the IP3 receptor1 (IP3R1), which results in the release of the Ca2+
through IP3R1, in turn, further contributing to already increased intracellular Ca2+
levels, resulting in synaptic dysfunction.
c) Dopamine acting on DA1 receptor activates adenosine 3',5'-cyclic monophosphate
(cAMP), which further activates protein kinase A (PKA). Upon PKA activation, the
intracellular Ca2+ levels increase through IP3R1. Additionally, PKA activates
dopamine- and cAMP-regulated neuronal phosphoprotein (DARRP-32) and
extracellular signal-regulated kinases (ERK), which alters cAMP response element-
binding protein (CREB) activity resulting in altered transcription and cognitive
impairment.
d) Dopamine acting on DA2 receptor further contributes to the intracellular Ca2+ levels
through the activation of IP3R1. This Ca2+ influx simultaneously activates
CALCINEURIN followed by glycogen synthase kinase 3β (GSK-3β) activation,
leading to the phosphorylation of TAU. This event results in impaired cognition and
cell death.