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7/31/2019 Parkinsons Disease credit seminar
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Parkinsons disease is a common, slowly progressive, neurodegenerativedisease. It results from the degeneration of neurons in the substantia nigra,
a region of the brain that controls movement.
This degeneration results in a shortage of a neurotransmitter called
dopamine, therefore, causing impaired movement.
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Substantia nigra, a distinct nucleus of the
midbrain, provides important input to a
portion of the basal ganglia that regulates
voluntary movements.
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Dopamine, is a major monoaminergic transmitter in the central nervous system.
The majority of dopaminergic neurons have their cell bodies in the substantia nigra while theiraxons project to the corpus striatum. Dopaminergic neurons have been implicated in the
regulation of motor behaviorthe degeneration of dopaminergic neurons underlies
Parkinson's disease, a debilitating disorder of movement
Gene knockout techniques have been applied to this system. In one set of experiments
the ability of neurons to synthesize dopamine was blocked by selectively inactivating the gene
that encodes tyrosine hydroxylase, one of the enzymes important in dopamine synthesis.The dopamine-deficient mice were born, began to nurse, and grew normally for about
two
weeks and then became inactive, failed to eat or drink, and died shortly thereafter.
However,
daily administration of L-DOPA, the product of tyrosine hydroxylase, restored normalfeeding
and produced increased activity.
WHY DOPAMINE IS IMPORTANT
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Genetic predisposition: The inheritance of a gene passed down from a
previous generation .
Free radicals: are unstable molecules produced during normal chemicalreactions in the body. When these molecules interact with other molecules
they have the ability to damage a variety of tissue types, including
neurons.
Environmental toxins: This has been seen in people who took an illegaldrug contaminated with a chemical called, MPTP. These individuals
developed severe Parkinson-like symptoms
MPTP is structurally similar to some pesticides.A breakdown product ofMPTP, called MPP+ is toxic to substantia nigra neurons
.
Accelerated aging: As a person ages, there is a normal wearing away ofdopamine producing neurons, which leads to the premature loss of
dopamine.
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ALPHA-SYNUCLEIN
PARKIN
DJ-1
DRDN
PINK-1
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-Synuclein (-SN) is a ubiquitous 140-amino acid protein that is abundant inneurons, especially at the presynaptic terminals and was also found to be the
main component of Lewy bodies.it is promotes accumulation of other Lewy
bodies
-SN plays dual roles of neuroprotection and neurotoxicity depending on itsconcentration or level of expression. At nanomolar concentrations, -SN protected
neurons against serum deprivation, oxidative stress.
both low micromolar and overexpressed levels in the cell, -SN resulted in
cytotoxicity
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.
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parkin interacts with synphilin-1 and alphasynuclein and mediates an
important step in protein handling.
parkin, DJ-1, DRDN, and PINK1 these extra genes cause overproductionof alpha-synuclein which can accumulate inside brain cells.
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Major symptomsThere are four symptoms that the majority of Parkinsons disease patients
experience.
Rigidity: stiffness when an arm, leg, or the neck is moved. The muscles remainconstantly tensed and contracted, so the person feels stiff and/or weak.
Resting tremor: a tremor which occurs when the person is at rest. This oftenbegins with an occasional trembling of one hand, most obvious when the person
is at rest or under stress.
Bradykinesia: slowness in initiating movement. This may also contribute todecreased facial movement, change in speech, shuffling gait and trouble with fine-
fingered movements.
Loss of postural reflexes or postural instability: resulting in poor balance andcoordination. Patients sometimes develop a forward or backward lean and fall
easily. This can also cause stooped posture, bowed head and drooped shoulders.
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TREATMENT OPTIONS
AVAILABLE
1. DOPAMINE AGONISTS ALONE2. DOPAMINE AGONISTS WITH ADJUNCTS
3. DEEP BRAIN STIMULATION
UNDER CLINICAL TRIAL
GENE THERAPY
UNDER PRELIMNARY RESEACH
STEM CELL THERAPY
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Medicationsare used to relieve the symptoms of Parkinsons disease. The type and dosage of
each medication is tailored to each persons individual needs.
Levodopa (L-dopa). Nerve cells use l-dopa to make and replenish the brains supplyof dopamine. L-dopa is often given along with carbidopa. Carbidopa delays the
conversion of levodopa into dopamine until it reaches the brain. This prevents, or
diminishes some of the side effects of L-dopa and reduces the amount of L-dopaneeded. L-dopa delays the onset of debilitating symptoms and allows many patients
to extend the period of time they are able to live normal lives. Bradykinesia and
rigidity respond best and tremor may be only slightly reduced.
Adverse effects such as nausea, vomiting, postural hypotension, involuntary
movements, restlessness, and cardiac arrhythmias.
wearing-off effect; that is, the re-emergenceof symptoms that occurs in some patients before their
next scheduled dose of levodopa.
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In DBS electrodes are implanted into the brain and connected to a small electricaldevice called a pulse generator that can externallysends electrical impulses to brain
to stimulate the subthalamic nucleus .
DBS reduces the need for levodopa and related drugs, which in turn decreases the
involuntary movements called dyskinesia's that are acommon side effect of levodopa. It also helps to alleviate
fluctuations of symptoms and to reduce tremors,
slowness of movements.
Complications include: brain hemorrhage, seizures, death.
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viruses are engineered to deliver genes that increase the supply of dopamine,
prevent cell death, or promote regeneration of neurons.
Mostly by using AAV ,lenti viral vectors we deliver the therapeutic gene
Still in clinical trails
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Stem cells obtained from blasto cytes, fibroblasts, bone marrow, or the adult,
embryonic, or fetal central nervous can form dopaminergic neuro blasts.
Several practical problems act as hurdles to successful stem cell therapy. Efficient
generation of dopamine producing neurons and successful grafting are required
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Parkinsons disease an article by national institute of health Alpha- synuclein: from secretion to dysfunction and death: O Marques1 and TF
Outeiro*
Managing the patient with newly diagnosed Parkinson disease: carlos singer
Adjunctive therapy in Parkinsons disease:Kathryn D Gaines1 Vanessa K Hinson2
Parkinsons Disease, Gene Therapies : philippe G. Coune, Bernard L. Schneider,
and Patrick Aebischer
Stem cell therapy for human neuro degeneretive disorders : olle lindvall, zall
kokaia and Alberto martinez-serrano
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