Abstract
During the past 30 years, a number of different hypotheses on cause of neuronal degeneration and dysfunction in Parkinson’s disease have been intensively investigated. Roles have been postulated for oxidative stress, excitotoxcity, nitric oxide, mitochondrial dysfunction, and inflammation. The possibility of an environmental cause was highlighted by the discovery of a simple molecule known as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a compound that is selectively toxic to the same cells in the brain that die in Parkinson’s disease. Yet the most recent hypothesis to come under scrutiny did not emerge from any of this previous work, but rather from a rare form of genetic parkinsonism known as PARK 1. This form of autosomal dominant parkinsonism is caused by mutations in the gene that encodes for the protein α-synuclein. Unexpectedly, this protein has been found to accumulate in nerve cells and their processes in all patients with Parkinson’s disease, raising the possibility that abnormal protein folding and aggregation represent a fundamental feature of the disease. These observations have already ushered in a new era of research on the disease and stimulated novel strategies directed toward disease modification by providing new therapeutic targets for drug development. Only time will tell if this most recent chapter in the search for the molecular basis of neurodegeneration in Parkinson’s disease will be one that holds the key to understanding this complex disorder and the highly characteristic pattern of selective vulnerability exhibited by the neuronal populations it affects. But an exciting body of accumulating scientific evidence is pointing in that direction.
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Langston, J.W. (2007). Progress in Understanding the Mechanisms of Neuronal Dysfunction and Degeneration in Parkinson’s Disease. In: Uversky, V.N., Fink, A.L. (eds) Protein Misfolding, Aggregation, and Conformational Diseases. Protein Reviews, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-36534-3_3
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