Parkinsons disease is a common, slowly progressive, neurodegenerative disease.

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.

Substantia nigra, a distinct nucleus of the midbrain, provides important input to a portion of the basal ganglia that regulates voluntary movements.

WHY DOPAMINE IS IMPORTANT

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 their axons 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 normal feeding and produced increased activity.

Genetic predisposition: The inheritance of a gene passed down from a previous generation .

Free radicals: are unstable molecules produced during normal chemical reactions 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 illegal drug contaminated with a chemical called, MPTP. These individuals developed severe Parkinson-like symptoms MPTP is structurally similar to some pesticides.A breakdown product of MPTP, called MPP+ is toxic to substantia nigra neurons . Accelerated aging: As a person ages, there is a normal wearing away of dopamine producing neurons, which leads to the premature loss of dopamine.

ALPHA-SYNUCLEIN

PARKIN
DJ-1 DRDN PINK-1

-Synuclein (-SN) is a ubiquitous 140-amino acid protein that is abundant in neurons, 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 its concentration 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

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 overproduction of alpha-synuclein which can accumulate inside brain cells.

Major symptoms There are four symptoms that the majority of Parkinsons disease patients experience. Rigidity: stiffness when an arm, leg, or the neck is moved. The muscles remain constantly tensed and contracted, so the person feels stiff and/or weak. Resting tremor: a tremor which occurs when the person is at rest. This often begins 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 to decreased facial movement, change in speech, shuffling gait and trouble with finefingered movements. Loss of postural reflexes or postural instability: resulting in poor balance and coordination. Patients sometimes develop a forward or backward lean and fall easily. This can also cause stooped posture, bowed head and drooped shoulders.

TREATMENT OPTIONS

AVAILABLE 1. DOPAMINE AGONISTS ALONE 2. DOPAMINE AGONISTS WITH ADJUNCTS 3. DEEP BRAIN STIMULATION
UNDER CLINICAL TRIAL GENE THERAPY UNDER PRELIMNARY RESEACH STEM CELL THERAPY

Medications are 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 supply of 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-dopa needed. 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-emergence of symptoms that occurs in some patients before their next scheduled dose of levodopa.

In DBS electrodes are implanted into the brain and connected to a small electrical device called a pulse generator that can externally sends 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 a common 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.

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

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

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