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

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

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Inflammation / etiology
  • Lipids
  • Mutation / genetics
  • Neurons / cytology
  • Neurons / metabolism*
  • Parkinson Disease / complications
  • Parkinson Disease / etiology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology*
  • Secretory Vesicles / genetics
  • Secretory Vesicles / metabolism
  • Secretory Vesicles / pathology
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Lipids
  • alpha-Synuclein