Parkinson’s Disease credit seminar

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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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

Documents

Parkinson’s Disease credit seminar