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From the Genetic Pharmacology Unit, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Address correspondence and reprint requests to Dr. M. Maral Mouradian, NINDS, NIH, 10 Center Drive, MSC 1406, Bethesda, MD 20892-1406; e-mail: MouradianM{at}ninds.nih.gov
The identification of three genes and several additional loci associated with inherited forms of levodopa-responsive PD has confirmed that this is not a single disorder. Yet, analyses of the structure and function of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the common mechanism leading to neurodegeneration in all known forms of this disease. The three specific genes identified to date—
-synuclein, Parkin, and ubiquitin C terminal hydrolase L1—are either closely involved in the proper functioning of the ubiquitin-proteasome pathway or are degraded by this protein-clearing machinery of cells. Knowledge gained from genetically transmitted PD also has clear implications for nonfamilial forms of the disease. Lewy bodies, even in sporadic PD, contain these three gene products, particularly abundant amounts of fibrillar -synuclein. Increased aggregation of -synuclein by oxidative stress, as well as oxidant-induced proteasomal dysfunction, link genetic and potential environmental factors in the onset and progression of the disease. The biochemical and molecular cascades elucidated from genetic studies in PD can provide novel targets for curative therapies.
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