α-Synuclein impairs macroautophagy: implications for Parkinson's disease

J Cell Biol. 2010 Sep 20;190(6):1023-37. doi: 10.1083/jcb.201003122.

Abstract

Parkinson's disease (PD) is characterized pathologically by intraneuronal inclusions called Lewy bodies, largely comprised of α-synuclein. Multiplication of the α-synuclein gene locus increases α-synuclein expression and causes PD. Thus, overexpression of wild-type α-synuclein is toxic. In this study, we demonstrate that α-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Our data show that α-synuclein compromises autophagy via Rab1a inhibition and Rab1a overexpression rescues the autophagy defect caused by α-synuclein. Inhibition of autophagy by α-synuclein overexpression or Rab1a knockdown causes mislocalization of the autophagy protein, Atg9, and decreases omegasome formation. Rab1a, α-synuclein, and Atg9 all regulate formation of the omegasome, which marks autophagosome precursors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Cell Line, Tumor
  • Drosophila melanogaster / metabolism
  • Gene Knockdown Techniques
  • Golgi Apparatus / metabolism
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Phagosomes / metabolism
  • Protein Transport
  • Secretory Vesicles / metabolism
  • alpha-Synuclein / metabolism*
  • rab1 GTP-Binding Proteins / metabolism

Substances

  • Membrane Proteins
  • Microtubule-Associated Proteins
  • alpha-Synuclein
  • light chain 3, human
  • rab1 GTP-Binding Proteins