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Highlights from research breakthroughs in 2011Click

Here

Bernice Ramsay recipients announcedClick

Here

First Bernice Ramsay recipient publishes studyClick

Here

Effects of vitamin D deficiencyClick

Here

Ventilation education programClick

Here

FUS mutation can lead to Juvenile ALSClick

Here

Newly identified protein’s role in ALSClick

Here

Cell-based models manipulated into astrocytesClick

Here

ALS Society of Canada3000 Steeles Avenue East, Suite 200, Markham, Ontario L3R 4T9

Toll Free:1-800-267-4257 Telephone: 905-248-2052 Website: www.als.ca

WALK for ALS: www.walkforals.ca Golf for ALS: www.golfforals.ca

Most people diagnosed with ALS lose the ability to use their legs in the first two years of the disease...

“WhAt WouLd You do, WhiLe You StiLL CouLd?”

SPRING 2012

The LINC studyClick

Here

The “How to” Health GuideClick

Here

Canadian Neuromuscular Disease RegistryClick

Here

Axonal transport deficits and degenerationClick

Here

Eighth Annual Research ForumClick

Here

Goodbye – Denise FiglewiczClick

Here

ALS SOCIETY OF CANADA

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A Landmark Year in the History of

ALS Research

While advances in ALS research over the past

three years have been outstanding, 2011 was a

year of multiple exciting breakthroughs many

are calling a true turning point for ALS

research worldwide. These new findings build

on steady advances in fields as diverse as

biomarkers (substances which indicate a

biological state); the extraction and use of stem

cells to potentially restore function; advanced

imaging techniques; the role of environmental

toxins and genetic sensitivities; and complex

cell biology. With these new 2011 findings, we

have many more pieces of the puzzle – pieces

with the potential to enable earlier detection,

faster halting of symptoms, better drugs and

treatments and – with more investigation – the

possibility of partially restoring damaged

neural pathways.

ALS Canada salutes these global pathbreakers.

As you will see, many of them are Canadian –

a testimony to the community of outstanding

supporters and donors in Canada who are

making this country an international hub of

innovation and excellence worldwide. Here is a

summary of some of the most exciting

research results of 2011:

July 2011 – Sanjay Kalra, MD, University of

Alberta

Sanjay Kalra from University of Alberta’s

faculty of medicine and dentistry released two

studies that used advanced imaging to show

that ALS attacks multiple parts of the brain

and is not limited to the motor system. Kalra

used MRI scans to detect chemical changes

that indicate different aspects of the type of

degeneration seen in ALS, including death of

neurons and scarring (“gliosis”). These

advances have significant potential to track

ALS and its progression, enabling development

of more targeted treatments to slow or prevent

the disease in those parts of the brain which

are affected beyond the motor system.

September 2011 – Rosa Rademakers, PhD,

Mayo Clinic Jacksonville

A team led by Rosa Rademakers identified the

most common genetic cause known to date for

ALS and frontotemporal dementia. Results

show that a mutation of a single gene, called

C9ORF72, accounts for nearly 50 per cent of

the directly inherited familial ALS and Fronto

temporal Dementia (FTD) in the Finnish

population, and more than a third of familial

ALS in other groups of European ancestry.

Further studies by other groups have found

mutations in this gene in individuals with

sporadic (i.e., non-hereditary) ALS. Identifying

this defective gene provides important insights

into the complex interplay between genetic risk

for the disorder and other factors which

contribute to disease onset and progression.

These insights pave the way for a better

understanding of ALS and FTD biology and

the therapeutics that can be developed to

counteract it. University of British Columbia’s

Ian MacKenzie, MD, was a key Canadian

contributor to the study.

September 2011 – Neil Cashman, MD,

University of British Columbia

In healthy individuals, special enzymes protect

cells from dangerous free radicals. But

malformed enzymes, such as those found in

ALS, may have the opposite effect, in essence

initiating damage rather than protecting against

attack by dangerous free radicals, in a twisted

game of molecular tag. Neil Cashman and

colleagues at the University of British

Columbia reported in 2011 on their use of a

truncated enzyme and special antibodies to

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highLightS froM reSeArCh BreAkthroughS in 2011

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analyze the folding and misfolding of a key

protein. The goal is to create new proteins with

binding capacity to act as a “sticky patch”

where “bad” enzymes can attach and be

removed from the system. With further

development, these proteins have the potential

to block unhealthy interactions, thereby

stopping disease progression in its tracks.

November 2011 – Jean-Pierre Julien, PhD,

Université Laval

ALS is characterized by a degeneration of

neurons that control muscle activity. By

studying the spinal cords of people who died

from ALS, Julien’s team discovered an

overproduction of a protein called TDP-43 in

their nerve tissues. This protein can play a key

role: when it is “overexpressed,” it exaggerates

the inflammatory response that increases the

vulnerability of nerve cells to toxic molecules

that circulate in the body. The team is testing

an inhibitor that could lead to the development

of drugs to reduce this inflammation and

partially restore the neuromuscular function.

These are just a few of the most recent

breakthroughs. For more on Canadian ALS

research, please go to:

http://www.als.ca/sites/default/files/files/ALS

%20Canada%20Research%20Funding(1).pdf

BerniCe rAMSAY reCipientS AnnounCed

ALS Society of Canada is pleased to announce

the recipients of the 2011 Bernice Ramsay

Grants to three Canadian research projects.

Made possible by the generous estate of

Bernice Ramsay, which contributed $2.3 million

to ALS Canada in 2006, each recipient receives

a one-time grant to pursue innovative avenues

in ALS research.

The recipients of the fourth annual Bernice

Ramsay Discovery Grants are: University of

Alberta researchers Sanjay Kalra, MD, and

Herbert Yang, PhD; and University of

Montreal researchers Edor Kabashi, PhD, and

Pierre Drapeau, PhD.

The University of Alberta researchers’ project

is entitled, “Characterization of cerebral

degeneration in ALS using MRI-based texture

analysis.” The University of Montreal

researchers’ project is entitled,

“Characterization of C90RF72 intronic

expansions and genetic interaction with

TDP-43.”

Commencing in 2008, this multi-year initiative

funds two projects per year (each up to

$100,000) for the pursuit of new and promising

directions in ALS research.

Characterization of cerebral degeneration

in ALS using MRI-based texture analysis

There is currently no method of accurately

measuring the degenerative changes in the

brain of people living with ALS. Earlier

diagnosis and quicker access to treatment and

the efficiency of clinical trials would improve if

there was a way to quantify and monitor

cerebral degeneration in an ALS patient.

Kalra and co-investigator Yang will explore

different MRI techniques to cerebral

degeneration in ALS. The objective behind this

ALS Canada funded-study is to investigate

cerebral pathology using image texture analysis

to evaluate the extent and pattern of cerebral

involvement in those living with ALS. This

technique has not been employed in ALS

research. Kalra and Yang predict that texture

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analysis will reveal changes in MRI image

textures that differentiate ALS patients from

healthy controls. The researchers also predict

that the pattern of texture variations will be

different in ALS patients with cognitive

impairment compared to patients with intact

cognition. They further hypothesize that as the

disease progresses, the imaging will show

progression of in the texture variations.

Imaging data of different contrasts and of high

resolution will be acquired with a high field

magnet operating at 4.7 tesla (T). Compared to

most clinical scanners that operate at 1.5 T, this

high-field system will allow acquisition of

images of considerably higher resolution, thus

increasing the sensitivity of the proposed

method to detect degeneration. Their protocol

includes neurological and cognitive assessments

and an MRI repeated after six months.

This is a powerful and promising technique to

detect signatures of brain degeneration in MRI

images of patients with ALS. “Essentially, we

are looking for a biomarker – a quantitative

indicator of brain involvement that can be used

to diagnose ALS more quickly than current

methods and improve our understanding of its

pathobiology. Most importantly, I feel, is

finding a biomarker that can test novel

treatments more efficiently. All of these roles

of a biomarker can assist with the discovery of

new treatments,” explains Kalra.

Characterization of C9ORF72 intronic

expansions and genetic interaction with

TDP-43

Two independent studies have identified that

repeat expansions of a GGGGCC

hexanucleotide sequence in the non-coding

region of the C9ORF72 gene cause two

different but related neurodegenerative

diseases: ALS and frontotemporal dementia

(FTD), a disorder that primarily affects the

frontal and temporal lobes of the brain that are

generally associated with personality, behaviour,

and language. Nothing yet is known about the

biochemical and molecular functions of the

C9ORF72 gene. Earlier studies suggest the

repeat expansions of C9ORF72 may alter

mRNA splicing, leading to splice products

which could cause disease in motor neurons

and other cortical neurons.

An expanded section of repeated DNA

elements on chromosome 9 in the C9ORF72

gene was identified as the most common

known genetic cause of familial ALS (fALS),

familial FTD, and ALS-FTD, characterized by

changes in personality, behaviour, and

cognition, including executive and language

dysfunction.

The challenge for Kabashi and Drapeau is to

functionally characterize C9ORF72 intronic

repeats with major relevance to ALS. Their

research aims to develop animal models for the

repeat expansions of the C9ORF72 gene to

further understand the pathophysiological

mechanisms involved in ALS. To do this,

Kabashi and Drapeau will first determine

whether loss or gain of function by knocking

down C9ORF72 expression will lead to

neuronal degeneration using primary motor

neuron cultures, as well as the versatile animal

model, zebrafish.

Genetic models for the major genes in ALS,

TDP-43, FUS, and SOD1, have been

developed using zebrafish in the laboratory.

Stable transgenic models for C9ORF72

mutations will be developed to better

understand ALS pathophysiology. This will

help the researchers characterize C9ORF72

mutations to determine whether this gene will

interact with the three previously known major

genetic causes of ALS.

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The vertebrate zebrafish model is extremely

useful for performing drug screens to identify

therapeutic compounds for ALS patients.

Kabashi and colleagues have developed

zebrafish as a novel genetic model for ALS.

Zebrafish models are capable of rapid and

efficient genetic manipulation. Kabashi explains

the advantages of using zebrafish models as

“very useful to confirm whether a particular

gene may cause disease through loss of

function [by knocking down their expression

levels] or through a gain of function by

over-expressing the human mutant RNA.” The

embryos of this particular animal model

develop from egg to larvae within three days.

They are large and transparent, making it easier

for researchers to observe and study the

internal organs and tissues.

“These models will help us better understand

molecular mechanisms leading to

neurodegeneration, as well as, providing a

platform to identify chemical compounds with

neuroprotective properties,” explains Kabashi.

Bernice Ramsay Clinical Research

Fellowship

Amer Ghavanini, MD, PhD, is the 2011

recipient of the Bernice Ramsay Clinical

Research Fellowship. The fellowship will

commence in July 2012 in the neuromuscular

program of the London Health Sciences

Centre. His research project is entitled, “A new

method of estimation of the number of motor

units for clinical research in ALS.”

A new initiative beginning in 2009, the Bernice

Ramsay Clinical Research Fellowship program

supports specialized training in clinical care and

research skills related to ALS. The program

awards a researcher $100,000 per year for two

years.

A new method of estimation of the number of

motor units for clinical research in ALS

Ghavanini’s research will involve designing and

carrying out clinical studies, specifically to

develop new electrophysiological diagnostic

methods for monitoring and potentially

detection of ALS in the early clinical phase. “A

method that is sensitive, reliable and easy to

perform will significantly improve ALS clinical

trials,” says Ghavanini.

Current outcome measures for clinical

symptoms and signs used for ALS patients

show the course and history of the disease, but

do not directly measure the changes occurring

within the motor unit (MU) pool, a group of

MUs associated with a single muscle. MU

consists of a single alpha-neuron (lower motor

neurons) and the muscle fibres it stimulates. A

previous study by Shaun Boe, PhD, of

Sunnybrook Health Sciences Centre; Daniel

Stashuk, PhD, of the University of Waterloo;

and Timothy Doherty, MD, PhD, of London

Health Sciences Centre examined the use of

motor unit number estimation (MUNE) to

measure clinical outcomes of ALS. MUNE is a

non-invasive test that produces an estimated

number of functioning MUs in a muscle.

However, variations of MUNE are not widely

used in ALS clinical trials because “it is

burdensome and time-consuming,” explains

Ghavanini.

Ghavanini will investigate the estimated

number of MUs of healthy individuals

compared to ALS patients using fluctuation

analysis. In neurophysiology, this method has

been extensively used to estimate the number

of ion channels in a synapse from the variation

in the synaptic potential. Ghavanini explains,

“that fluctuation analysis can be applied to

peripheral nerve recordings to estimate the

number of motor units in a compound muscle

action potential, something that hasn't been

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done before.” The focus of the study is to

investigate the validity, reliability, and sensitivity

of fluctuation analysis.

Ghavanini has three specific objectives. The

first is to investigate the validity of fluctuation

analysis to estimate the number of MUs in

healthy subjects. He will compare fluctuation

analysis with decomposition-enhanced

spike-triggered averaging MUNE (DE-STA

MUNE) as the standard method. DE-STA

MUNE, a variation of MUNE, is a sensitive

and reliable outcome measure for ALS clinical

trials. Second, he will determine the reliability

of fluctuation analysis to estimate the number

of MUs in ALS patients. And third, the sensi-

tivity of fluctuation analysis to predict clinical

outcome of ALS patients will be investigated.

DE-STA MUNE will be used as the gold

standard. Twenty healthy subjects and 20 ALS

patients will be examined to estimate the

number of MUs and MU potential in the first

dorsal interosseus and tibialis anterior muscles.

Ghavanini will use similar stimulations and

recording sites for the fluctuation analysis

method.

“The results of these investigations will

establish the utility of a new and potentially

less burdensome electrophysiological method

[to estimate] the number of motor units. The

findings will potentially improve the outcome

measures for ALS clinical trials,” explains

Ghavanini.

After completing his fellowship in

neuromuscular disorders, Ghavanini hopes to

pursue an academic career within a team of

clinicians and scientists to provide clinical care

to those living with ALS, and to advance their

knowledge and develop new therapeutics for

ALS.

firSt BerniCe rAMSAY reCipient puBLiSheS StudY

The Bernice Ramsay Discovery Grants is a

five-year initiative that funds two projects per

year (each up to $100,000) for the pursuit of

new and promising directions in ALS research.

Made possible by the generous estate of

Bernice Ramsay, donating $2.28 million to ALS

Canada in 2006, each recipient receives a

one-time grant to pursue promising

developments towards ALS research. Alex

Parker, PhD, assistant professor in the

department of pathology and cell biology at

the University of Montreal, was one of the first

two recipients of the Bernice Ramsay

Discovery Grants. A geneticist by training,

Parker focuses on late-onset neurodegenerative

diseases. In 2007, he established his own

laboratory at the University of Montreal to

better understand the links between aging

process and neurodegeneration. Parker was

awarded the Bernice Ramsay Discovery Grant

in 2008 for his project, “Investigating the

physiological consequences of TDP-43

mutations in a simple model system.”

The Bernice Ramsay funding paved way for

Parker and colleagues at the University of

Montreal: Alexandra Vaccaro, MSc; Arnaud

Tauffenberger, MSc; Dina Aggad, PhD; Guy

Rouleau, MD, PhD; and Pierre Drapeau, PhD,

to successfully develop new C.elegans TDP-43

and FUS models. The study, entitled “Mutant

TDP-43 and FUS Cause Age-Dependent

Paralysis and Neurodegeneration in C.elegans,”

was recently published in the February 2012

online issue of PLoS ONE.

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TAR DNA-binding protein 43 (TDP-43) and

Fused in sarcoma (FUS) are two binding

proteins that are closely associated with ALS.

TDP-43 binds to other proteins and changes

the way they function. It can also bind to DNA

and RNA to regulate how proteins are

expressed. In 2006, TDP-43 was identified as a

component of protein clumps inside dying

neurons in ALS. Resembling TDP-43, FUS is

an RNA-binding protein that is also found in

cytoplasmic clumps in dying neurons in

sporadic and familial ALS.

To better understand the mechanisms of

TDP-43 and FUS toxicity, the researchers

created transgenic Caenorhabditis elegans

(C.elegans) strains expressing full-length,

untagged human TDP-43 and FUS in the

worm’s GABAergic motor neurons. These

transgenic worms, expressing mutant TDP-43

and FUS, displayed adult-onset, age-dependent

loss of motility, progressive paralysis, and

neuronal degeneration. The researchers also

developed a liquid culture assay where the

paralysis phenotype evolves over several hours.

C.elegans transgenics were introduced to

mutant TDP-43 and FUS motor neuron

toxicity to test for rapid genetic and

pharmacological suppressor screening.

Parker and colleagues concluded that transgenic

worms that expressed human TDP-43 or FUS

in motor neuron display age-dependent

paralysis. Transgenic TDP-43 and FUS models

had normal lifespans, with decreased in motility

as one of the signs of aging. TDP-43 and FUS

transgenics mimic the adult-onset, gradual

decline of neuronal function, resulting in

age-dependent motor neuron degeneration as

seen in ALS.

“These models are a direct result of the

Bernice Ramsay funding. What makes our

model different than the others is that we have

animals showing adult-onset, age-dependent

phenotypes. Plus, our models are highly

amenable to rapid in vivo drug screening,”

explains Parker.

For more information about this study, please

visit

http://www.plosone.org/article/info%3Adoi%

2F10.1371%2Fjournal.pone.0031321

reSeArCh updAteS

Effects of Vitamin D deficiency in a

transgenic mouse model of ALS

A new York University research study yielded

conflicting results about the effects of dietary

deficiency of Vitamin D from an early age in

the well-characterized G93A (mutant SOD-1)

transgenic mouse model of ALS. Deficiency of

Vitamin D improves early disease severity and

delays onset of ALS, but reduces performance

in functional outcomes following disease onset.

The research was conducted by graduate

students Jesse Solomon and Alexandro

Gianforcaro, supervised by Kinesiology

Professor Mazen Hamadeh. This study

appeared in the December 27th publication of

PLoS ONE.

This is the third in a series of studies from the

Hamadeh laboratory. In the previous studies,

the researchers found that an increased intake

of Vitamin D led to improved motor

performance and endurance yet no change in

the disease outcomes – progression and

lifespan.

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In this third study the authors found that the

vitamin D-deprived G93A mice did have a

greater loss of motor function. However they

found a later, not an earlier, age at onset. So

they hypothesize that the loss of Vitamin D

has a different effect on the motor neurons as

compared to the muscles. They will explore this

hypothesis in future studies.

For more information about the study, please

visit:

http://www.plosone.org/article/info%3Adoi%

2F10.1371%2Fjournal.pone.0029354

Ventilation education program helps with

real-life decisions

After a 10-year period of analysis, Douglas A.

McKim, MD, associate professor at the

University of Ottawa, and colleagues at The

Ottawa Hospital Rehabilitation Centre and

Pembroke Regional Hospital published a study

entitled, “Formal ventilation patient education

for ALS predicts real-life choices”. The focus

of the study was ventilatory support education

for patients and caregivers. The results were

published in the January 2012 online issue of

Amyotrophic Lateral Sclerosis.

The researchers’ objective was to evaluate a

single-session, hands-on education program on

mechanical ventilation for ALS patients and

caregivers. The program was designed to

observe whether decisions about ventilator use

made after the education program would reflect

real-life decisions. Questionnaires were given to

26 patients and 26 caregivers on four separate

occasions to assess their knowledge of ventila-

tory support, to get feedback on the nature of

the program, and to report the individual’s

emotional well-being.

Respiratory failure is a major cause of death for

those with ALS. Mechanical ventilatory support

provides an extended survival, but such

interventions come with serious ethical

decision-making dilemmas. Many patients do

not get the chance to discuss their wishes until

emergency intubation, when a tube is inserted

into an external or internal orifice of the body

to add or remove fluids or air. Conflict might

arise when there is no consent for interventions

in case of a respiratory failure.

It is important for ALS patients and caregivers

to understand the nature and limitations of

both non-invasive ventilation (NIV) and

invasive ventilation (IV). NIV is the

administration of ventilatory support without

using an invasive artificial airway, such as

endotracheal tube or tracheostomy tube, by

using a mask or nasal prongs to provide

ventilatory support through a patient’s nose or

mouth.

The results of the study showed that patients

and caregivers demonstrated improvements in

knowledge about ventilatory support. There

were also no changes in the self-reported

emotional well-being of the patient or

caregiver. The choices of ventilatory support at

one month reflected the real-life clinical choices

ultimately made by 76 per cent of patients. The

remaining patients chose palliative care.

The study clearly showed that the ventilation

education program gave those affected with

ALS and their caregivers the necessary

knowledge and information to make difficult

decisions. Instead of awaiting the onset of

respiratory failure, the program allowed

discussion of ventilatory choices available. The

result was reduced uncertainty by patients and

caregivers since they were better informed

regarding NIV and IV.

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The researchers concluded, “Hands-on patient

and caregiver education results in improved

knowledge, assists in decision-making with

respect to ventilatory support, and is not

associated with a worsening of affect. It also

provides for an accurate prediction of real-life

choices and avoids undesired life support

interventions and critical care admissions."

For more information about the study, please

click here.

FUS mutation can lead to Juvenile ALS

A study focusing on juvenile ALS (JALS) was

published in the January 16 online issue of

Archives of Neurology. This study was conducted

by a team of Montreal researchers: Veronique

Belzil, MSc; Jean-Sébastien Langlais, MD, MSc;

Hussein Daoud, PhD; Patrick Dion, PhD;

Bernard Brais, MD; and Guy Rouleau, MD,

PhD. The team sequenced all the coding exons

of SOD1, TARDBP, and FUS from a 19-year-

old patient who has JALS with a rapid course

of clinical progression.

JALS is generally associated with slow disease

progression, with neurodegeneration beginning

before the age of 25. Research in the past has

shown that a number of genes may be

responsible in causing JALS. Mutations in the

ALSIN gene caused JALS type 2 (ALS2), as

well as juvenile primary lateral sclerosis, and

infantile-onset ascending spastic paralysis.

Mutations in SETX gene are strongly

associated with JALS. On the other hand,

mutations in the SOD1, TARDBP, and FUS

genes typically cause pure ALS, with onset

between 46 and 56 years of age. However,

recent studies showed that a few mutations in

FUS are associated with juvenile-onset of ALS

that has very rapid progression.

The researchers found a novel 1-base pair

deletion in exon 14 of the FUS gene which led

to a frameshift and integration of 33 new

amino acids. The variant p.R495QfsX527 was

located in the conserved, extreme C terminal of

the FUS protein. This variant was also

identified in the unaffected 47-year-old mother

of the patient who showed no signs of the

disease. The researchers concluded that FUS

mutation can lead to an early-onset “malignant”

form of ALS. Data from the study also showed

that disruption of the conserved C terminal of

FUS is critical for the development of ALS.

For more information about the study, please

visit

http://archneur.ama-assn.org/cgi/content/

abstract/archneurol.2011.2499v1.

Newly identified protein may play an

important role in metabolic changes

associated with ALS

A new series of studies conducted by Robert

Kalb, MD, of the Children’s Hospital of

Philadelphia and University of Philadelphia

School of Medicine, and colleagues employed

in vitro and in vivo models of ALS to establish a

connection between expression of mutant

SOD1 or TDP-43 and changes in key

regulatory mechanisms for maintaining cellular

energy levels.

Studies in recent years have established that in

some mouse models of ALS, as well as in a

subgroup of ALS patients, there is an alteration

in the balance of energy expenditure which

cannot be accounted for by parameters

associated with ALS symptoms. AMP-activated

protein kinase (AMPK) is a key sensor of

cellular energy status and the authors

hypothesized that it might be activated in ALS

models.

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Their studies showed an increase of AMPK

activity in mixed cell cultures derived from

spinal cord, and in a mouse model, both of

which expressed mutant copper zinc

superoxide dismutase 1 (mSOD1), a gene

which is responsible for some familial ALS. By

adding an AMPK antagonist, the researchers

observed that they could prevent mSOD1-

induced motor neuron in vitro.

To further investigate the role of AMPK in vivo,

Kalb’s team used roundworm Caenorhabditis

elegans models (C.elegans) to express human

mSOD1. Locomotor activity – swimming and

crawling – was significantly reduced in these

transgenic worms. This functional loss was

partially rescued by knockdown of AMPK

activity. In further related experiments, the

authors used another worm model expressing a

mutant TDP-43 gene, which also underlies

some familial ALS. Similar to the mSOD1

models, these worms exhibited locomotor

defects which were partially reversed when

AMPK activity was reduced.

Taken together, these intriguing studies suggest

that AMPK, and related downstream pathways,

may provide the link between the gross

metabolic changes, muscle atrophy, and motor

neuron degeneration in ALS. These findings

may lead to a new direction in developing

treatment for ALS, as well as other

neurodegenerative disorders.

For more information about the study, please

click here.

Cell-based models manipulated into

astrocytes to test potential role in SALS

ALS is characterized by the degeneration of

motor neurons in the spinal cord and brain

stem. The most significant advances in

experimental mouse models have been based

on SOD1 mutations, accounting for

approximately two per cent of all cases.

Astrocytes, cells in the brain and spinal cord

that modulate neural functions, have been

found to play a role in the interaction of

familial ALS (FALS) caused by SOD1

mutations. Researchers have been scrambling to

develop a model that can provide insights into

the roles astrocytes play in sporadic ALS

(SALS), accounting for 90 per cent of all ALS

cases. Previous research studies suggest that

FALS and SALS motor neurons may

degenerate through similar mechanisms.

However, a cell-based model has not been

created to test the potential role of astrocytes

in SALS.

Led by Amanda Haidet-Phillips, MD, the

researchers from the Centre for Gene Therapy

at the Nationwide Children’s Hospital in Ohio

have addressed this issue by isolating cells from

a post-mortem ALS patients’ spinal tissue.

These cells, called progenitor stem cells, were

manipulated to develop into astrocytes. The

study, entitled “Astrocytes from familial and

sporadic ALS patients are toxic to motor

neurons,” was published in the August 10,

2011, online issue of Nature Biotechnology.

FALS and SALS stem cells were combined with

mouse motor neurons to observe their effect

on motor neuron degeneration. The study

analyzed seven SALS cultures without SOD1

mutation, one FALS culture containing the

SOD1 mutation, and healthy controls.

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After 120 hours, the co-culture of FALS with

astrocytes led to death in 50 per cent of the

motor neurons, compared to no death

observed in the controls. Similarly, co-culture

using astrocytes derived from all of the SALS

cultures led to a 45–70 per cent decrease of

motor neurons, compared to controls.

“The motor neuron damage elicited by the

SALS patient-derived astrocytes was

indistinguishable from that elicited by the FALS

astrocytes, suggesting a shared mechanism for

motor neuron death in both types of

co-cultures,” reports Haidet-Phillips.

To verify that astrocytes are key factor,

fibroblasts were cultured from ALS patients

using the same technique. As suspected, no

significant motor neuron loss was observed.

Additionally, FALS- and SALS-diseased

astrocytes did not affect the survival of other

neuronal cells, suggesting a specific interplay

between astrocytes and motor neurons.

It is unclear whether FALS and SALS

astrocytes are secreting a toxin, or depriving the

motor neuron of a factor essential to its

survival. Researchers examined the

inflammatory signal cascade which has been

implicated in prior studies involving FALS and

astrocytes. A diverse set of 84 genes,

responsible for inflammatory signals, was

analyzed in FALS- and SALS-derived

astrocytes. The inflammatory responses

increased 35–60 per cent compared to control

astrocytes. Specifically, a cluster of 22 genes

displayed upregulated activation, providing key

information for future studies. There was a

considerable overlap in the genes that were

involved in FALS and SALS.

Interestingly, when the researchers suppressed

the FALS SOD1 mutation in FALS-derived

astrocytes so that it was not active, survival of

co-cultured motor neurons mirrored that of

the healthy control. Suppression of SOD1 in

SALS cultures yielded a significant

neuroprotection in four of six SOD1 culture

lines. The other two lines also displayed a trend

toward neuroprotection compared to an intact

SOD1 culture, which is not significant. It is

speculated that in SALS, the normal SOD1

protein may assume conformational changes

that makes it react similar to the FALS mutant

form.

These links between astrocytes (SOD1, SALS,

and FALS) open exciting opportunities for

therapeutic developments with the potential to

help all 90 per cent of the ALS population.

Ultimately, understanding the mechanisms by

which astrocytes cause toxicity require

additional investigation. This study describes a

new model system which can be employed to

achieve that goal.

For more information about this study, please

visit

http://www.nature.com/nbt/journal/v29/n9/

pdf/nbt.1957.pdf.

Axonal transport deficits and degeneration

develop independently

Researchers from Munich, Germany published

a study entitled, “Axonal transport deficits and

degeneration can evolve independently in

mouse models of ALS,” that challenged a

widely accepted hypothesis about a potentially

contributing factor to neurodegenerative

diseases.

The study was led by Thomas Misgeld, MD,

PhD, professor at the Technische Universitaet

Muenchen (TUM), Institute of Neuroscience,

and Martin Kerschensteiner, MD, professor at

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the Ludwig-Maximilians-Universitaet

Muenchen (LMU), Institute of Clinical

Neuroimmunology. The results were published

on the February 27 online issue of Proceedings of

the National Academy of Sciences (PNAS). The

researchers used imaging techniques to observe

changes in both axon morphology and

organelle transport in several different animal

models of ALS.

Axonal transport deficits have been reported in

many neurodegenerative conditions, including

ALS, and are widely assumed to be an

immediate causative step to axon and synapse

loss. The authors stated, “By imaging changes

in axonal morphology and organelle transport

over time in several animal models of ALS, we

now find that deficits in axonal transport of

organelles (mitochondria, endosomes) and axon

degeneration can evolve independently.”

Studies linking organelle transport and ALS

have been limited. “These data suggest that

disturbances of organelle transport are not a

necessary step in the emergence of motor

neuron degeneration,” the researchers

concluded.

For more information about this study, please

visit

http://www.pnas.org/content/early/2012/02/

22/1200658109.full.pdf.

Canadian Neuromuscular Disease Registry

(CNDR)

In June 2011, a new national registry (The

Canadian Neuromuscular Disease Registry

(CNDR) for patients with neuromuscular

disease will help patients connect with

researchers to participate in clinical research

that will benefit patients by offering possible

new therapies, treatments and understanding of

their disease.

“This is a tremendous opportunity for patients,

healthcare professionals, and researchers, to

connect and improve research into

neuromuscular diseases across Canada” says

Lawrence Korngut, MD, the national principal

investigator from the University of Calgary’s

Faculty of Medicine, and a member of the

Hotchkiss Brain Institute.

The CNDR is a Canada-wide database of

patients who have been diagnosed with a

neuromuscular disease. The term

“neuromuscular disease” refers to a group of

more than 40 diseases that affect how muscles

and nerves work. ALS is the most prominent

of these diseases in adults, and and Duchenne

muscular dystrophy (DMD) is the most

common pediatric muscular dystrophy.

The Canadian Neuromuscular Disease Registry

(CNDR) includes 17 clinics across Canada

located in Vancouver, Calgary, Edmonton,

Ottawa, Toronto, London, Kingston, Montreal

and Halifax.

Why participate?

The Registry is the only means by which valid

national epidemiologic data about ALS can be

obtained.

Patients with neuromuscular disease will benefit

from this new national registry. Shelagh

Mikulak has ALS and joined the registry

because it gives her hope that “with the

information available to researchers there will

be a significant increase in the number of

studies leading to discovering the cause,

treatment and cure of ALS”.

Finding treatments for neuromuscular diseases

has been challenging, as patients are scattered

across the country. This registry will allow

doctors and researchers to look at medical data

from large groups of patients helping them to

find better ways to manage each disease.re

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All patients both adults and children across

Canada who have been diagnosed with a

neuromuscular disease are able to join the

registry. Patients living outside the cities with

affiliated clinics, or those not currently seeing a

neuromuscular specialist, can register by

contacting the CNDR National Office at the

University of Calgary at 1-877-401-4494.

The CNDR is supported by the ALS Society of

Canada, Jesse’s Journey and the Marigold

Foundation.

For more information about the registry please

visit www.cndr.org.

The LINC study

The LINC Study is a national study to learn

about people living with a neurological

condition and how it impacts their everyday

lives.

The LINC Study has three parts:

1. A snapshot in time: an in-depth survey of

3500 people living in Canada.

2. A year in the life of 350 Canadians: a series

of monthly conversations.

3. Individual stories: a study of 18 people,

their families and supporters.

To participate in the study, please visit

http://occupationaltherapy.dal.ca/The%20LIN

C%20Study/

The “How-to” Health Guide

The “How To” Health Guide was developed by

the Health Charities Coalition of Canada to

assist patients, caregivers, friends and families in

managing information about the Canadian

health care system, which can often be

challenging to navigate. If you, or someone you

love and care for, are trying to find health

services, support or information for an illness

or disease, there are actions you can take to

help get the best possible health care.

The Guide provides basic information about

how to speak to those working within the

system on a range of issues, including how to:

• Understand the health care system

• Find the information and services you need

• Review and Evaluate the information you

find

• Talk with your doctor or health care

provider

• Ask for a second opinion

• Manage your condition

• Pay for your medication

• Participate in a clinical trial

• Advocate and ask for the support you need

Please visit www.als.ca to download the guide.

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eighth AnnuAL reSeArCh foruM

Planning for the 8th Annual ALS Research Forum is underway. Scheduled to be

held at the Toronto Airport Gateway Sheraton Hotel, April 28–30, 2012, five

plenary speakers will anchor the program – Christopher Henderson, PhD,

(Columbia University); Daryl Bosco, PhD, (University of Massachusetts); Tim

Miller, MD, PhD, (Washington University St. Louis); Sarah Kulke, MD, (Biogen

Idec); and Christopher Pearson, PhD, (University of Toronto).

Their talks will range from stem cells to clinical trials. The purpose of the

forum is to promote discussion among members of the Canadian ALS research

community on the underlying biology of ALS, the development of effective

therapies, and the improvement of the quality of care for people living with

ALS and their families, with a focus on how the ALS Society of Canada can

best facilitate these efforts. ALS Canada is committed to encouraging young

Canadians to join the growing number of researchers seeking a cure/treatment

for ALS. The ALS Research Forum is an excellent opportunity for the more

than 100 researchers to meet other ALS researchers and network with

colleagues in the ALS field.

goodBYe – deniSe figLeWiCzGoodbye and Best Wishes to Denise Figlewicz, PhD, VP, Research,

ALS Society of Canada

Denise Figlewicz has left the ALS Society of Canada after five years of

dedicated service. Figlewicz has raised the profile of ALS research during her

tenure. She has taken on a new role as vice dean, research and innovation, at the

Schulich School of Medicine, University

of Western Ontario. We wish her every

success in her new endeavours.

A search is currently being conducted

to replace Denise Figlewicz.

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Contact ALS Society of Canada • 1-800-267-4257

Lindee david, CEO........................................ld@als.ca.....ext. 206

enzo raponi, Director Development...................er@als.ca.....ext. 205

Bobbi greenberg, Director Communications.........bg@als.ca.....ext. 208

Jane McCarthy, Director Service and Education.....jm@als.ca.....ext. 230

karen hunter, Director Finance.........................kh@als.ca.....ext. 207

darija ilic, Senior Manager Direct Response...........di@als.ca.....ext. 203

Andrew romano, Manager, Projects and Events.....ar@als.ca.....ext. 210

indra patterson, Administrative Assistant............iwp@als.ca.....ext. 201

kim Wosnick, Events Co-ordinator.....................kw@als.ca.....ext. 219

grechen geronimo, Fund Development Assistant...gg@als.ca.....ext. 204

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