Alpha-Synuclein is degraded by both autophagy and the proteasome

J Biol Chem. 2003 Jul 4;278(27):25009-13. doi: 10.1074/jbc.M300227200. Epub 2003 Apr 28.

Abstract

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates (Lewy bodies) in neurons. alpha-Synuclein is the major protein in Lewy bodies and rare mutations in alpha-synuclein cause early-onset PD. Consequently, alpha-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of alpha-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T alpha-synuclein can be switched on and off. We have used a panel of inhibitors/stimulators of autophagy and proteasome function and followed alpha-synuclein degradation in these cells. We found that not only is alpha-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of alpha-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of alpha-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Autophagy / drug effects
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / metabolism
  • Humans
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / metabolism
  • Nerve Tissue Proteins / metabolism*
  • PC12 Cells
  • Proteasome Endopeptidase Complex
  • Rats
  • Sirolimus / pharmacology
  • Synucleins
  • alpha-Synuclein

Substances

  • Antibiotics, Antineoplastic
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • SNCA protein, human
  • Snca protein, rat
  • Synucleins
  • alpha-Synuclein
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Sirolimus