Clues to how alpha-synuclein damages neurons in Parkinson's disease.
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.
Sulzer
David
D
Department of Neurology, Columbia University Medical School, New York State Psychiatric Institute, New York, New York 10032, USA. ds43@columbia.edu
D006801:Humans; D007249:Inflammation / Q000209:etiology; D008055:Lipids; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010300:Parkinson Disease / Q000150:complications / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D008055:Lipids; D051844:alpha-Synuclein