Parkinson's disease

Parkinson's disease (PD; paralysis agitans) is a neurodegenerative disease of the substantia nigra (an area in the basal ganglia of the brain). The disease was first discovered and its symptoms documented in 1817 (An Essay on the Shaking Palsy) by the British physician Dr. James Parkinson; the associated biochemical changes in the brain of patients were identified in the 1960s. Some genes were identified only recently; others remain unknown.

Causes

The cause of Parkinson's disease is not known. Geneticists have since 1997 found nine different specific genetic defects, each of which causes the disease in one or a few families with extraordinarily high incidences of the disease, but such families are rare. While a strong inheritance pattern occurs in only a very small percentage of cases, an affected individual is three to four times more likely than an unaffected individual to have a close relative with Parkinson's. Having a parent with Parkinson's raises one's lifetime risk of developing the disorder threefold, from the general population's figure of 2% to about 6%. Genes that have been identified include SNCA (protein alpha-synuclein), UCHL1 (protein ubiquitin carboxy-terminal hydrolase L1), PARK2 (protein parkin), and PARK7 (protein DJ-1). Indeed, recent linkage studies excluded most of the above gene defects from consideration in the causation of sporadic (i.e. non-familial) Parkinson's disease, which constitutes more than 95% of cases. Most recently, a new gene was identified, ND5, mutation in which is thought to account for a vast majority of sporadic PD cases (see below).

Related Topics:
Geneticist - 1997 - Incidence - Protein - Alpha-synuclein - Ubiquitin carboxy-terminal hydrolase L1 - Parkin - DJ-1

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A popular theory holds that the disease might result in most cases from the combination of a subtle genetically determined vulnerability to environmental toxins along with mild exposure to those toxins. The toxins most strongly suspected at present are certain pesticides and industrial metals. MPTP is used as a model for Parkinson's as it can rapidly induce parkinsonian symptoms in patients/animals of any age. Other toxin-based models employ paraquat (an herbicide) or rotenone (an insecticide). Studies have found a mild increase in PD in persons chronically exposed to these agricultural chemicals.

Related Topics:
Toxin - Pesticide - MPTP - Paraquat - Rotenone

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Almost all of the PD-causing toxins act on the mitochondrial complex I of the electron transfer chain, and sporadic PD cases have been found to have a partial loss of activity of this enzyme complex. Studies in cybrids found that mitochondrial DNA, rather than the nuclear DNA is responsible for the dysfunction. Most recently, microheteroplasmic mutations in one of the mitochondrial complex I genes, ND5, were found to be sufficient to diagnose sporadic PD correctly in 27 out of 28 cases. While additional studies are needed, mitochondrial microheteroplasmic mutations may represent the true cause of the vast majority of PD cases.

Related Topics:
Mitochondrial - Complex I - Electron transfer chain - Cybrid - Mitochondrial DNA - Microheteroplasmic

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Minor past episodes of head trauma are also more commonly reported by sufferers than by others in the population. While emotional or a psychological trauma can precipitate the initial symptoms or aggravate existing symptoms, this is not the actual cause of the disorder.

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The symptoms of Parkinson's disease result from the loss of dopamine-secreting (dopaminergic) cells and subsequent loss of melanin, secreted by the same cells, in the pars compacta region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to inhibition of the direct pathway of movement and activation of the indirect pathway of movement. Since the direct pathway facilitates movement and the indirect pathway inhibits movement, the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in an excessive inhibition of the thalamus, leading to hypokinesia.

Related Topics:
Dopamine - Melanin - Pars compacta - Striatum - Direct pathway of movement - Indirect pathway of movement - Hypokinesia

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Brain cells producing other brain chemicals such as GABA, norepinephrine, serotonin and acetylcholine exhibit minor damage in Parkinson's disease, accounting for some of the wide array of symptoms.

Related Topics:
GABA - Norepinephrine - Serotonin - Acetylcholine

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The mechanism by which the brain cells in Parkinson's are lost appears to center on an abnormal accumulation of the protein alpha-synuclein in the damaged cells. This protein forms proteinaceous cytoplasmic inclusions called Lewy bodies. The precise mechanism whereby aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. It does appear that alpha-synuclein aggregation is enhanced by the presence of dopamine and the byproducts of dopamine production. Based on this mechanistic hypothesis, a transgenic mouse model of Parkinson's has been generated by introduction of human wild-type α-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.{{ref|PDmousemodel}}

Related Topics:
Alpha-synuclein - Lewy bodies - Transgenic mouse model - Platelet-derived-growth factor

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