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Mov Disord. 2010;25 Suppl 1:S27-31. doi: 10.1002/mds.22639.

Clues to how alpha-synuclein damages neurons in Parkinson's disease.

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Department of Neurology, Columbia University Medical School, New York State Psychiatric Institute, New York, New York 10032, USA.


Alpha-synuclein (alpha-syn) appears to normally regulate neurotransmitter release, possibly via calcium-dependent binding and dissociation from lipid domains on secretory vesicles. The pathogenic effects of alpha-syn leading to Parkinson's disease (PD) appear to result from alternate toxic effects on lipid membrane. A variety of findings indicate that overexpression of wild-type alpha-syn, pathogenic mutations of alpha-syn, and dopamine-modified-alpha-syn promote toxic interaction between alpha-syn oligomers and lipids. These may disrupt transmembrane concentration gradients across secretory vesicles and other organelles and interfere with normal lysosomal or ubiqutin/proteasome mediated protein degradation or mitochondrial function. Additional causes of PD may interfere at other points with normal handling and degradation of alpha-syn, providing a variety of entry points to a converging neurodegenerative path underlying the disease.

[Indexed for MEDLINE]

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