alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome

FEBS Lett. 2001 Nov 30;509(1):22-6. doi: 10.1016/s0014-5793(01)03115-5.


alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations in familial cases of the disease and its presence in Lewy bodies. Here we show that over-expression of wild-type human alpha-synuclein is sufficient to induce inclusion formation in SH-SY5Y cells. In this cellular model, proteasome inhibition leads to an increase of alpha-synuclein accumulation in vivo without ubiquitylation. In accordance, we find that in vitro, unmodified alpha-synuclein can be directly degraded by the 20S proteasome. These findings suggest an ubiquitin-independent mechanism of proteasomal degradation for alpha-synuclein and other natively unfolded proteins.

MeSH terms

  • Cysteine Endopeptidases / metabolism*
  • DNA, Complementary / metabolism
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Microscopy, Electron
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Parkinson Disease / metabolism
  • Plasmids / metabolism
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Denaturation
  • Protein Folding
  • Recombinant Proteins / metabolism
  • Synucleins
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Ubiquitin / metabolism*
  • alpha-Synuclein


  • DNA, Complementary
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • SNCA protein, human
  • Synucleins
  • Ubiquitin
  • alpha-Synuclein
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex