Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation

J Neurol Sci. 2011 Aug 15;307(1-2):157-61. doi: 10.1016/j.jns.2011.04.015. Epub 2011 Jun 8.


Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are characterized pathologically by intraneuronal inclusions called Lewy bodies (LBs) and Lewy neurites. A major component of these inclusions is the protein α-synuclein, which is natively unfolded but forms oligomers and insoluble fibrillar aggregates under pathological conditions. Although α-synuclein is known to undergo several posttranslational modifications, the contribution of SUMOylation to α-synuclein aggregation and the pathogenesis of α-synucleinopathies have not been elucidated. Here, we provide evidence that aggregates and inclusions formed as a result of impaired proteasome activity contain SUMOylated α-synuclein. Additionally, SUMO1 is present in the halo of LBs colocalizing with α-synuclein in the brains of PD and DLB patients. Interestingly, SUMOylation does not affect the ubiquitination of α-synuclein. These findings suggest that proteasomal dysfunction results in the accumulation of SUMOylated α-synuclein and subsequently its aggregation, pointing to the contribution of this posttranslational modification to the pathogenesis of inclusion formation in α-synucleinopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Humans
  • Inclusion Bodies / enzymology
  • Inclusion Bodies / metabolism*
  • Inclusion Bodies / pathology
  • Lewy Bodies / enzymology
  • Lewy Bodies / metabolism
  • Lewy Bodies / pathology
  • Lewy Body Disease / enzymology
  • Lewy Body Disease / metabolism*
  • Lewy Body Disease / physiopathology
  • Macromolecular Substances / metabolism
  • Parkinson Disease / enzymology
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Proteasome Endopeptidase Complex / physiology
  • Proteasome Inhibitors*
  • Protein Processing, Post-Translational / physiology
  • SUMO-1 Protein / metabolism*
  • Sumoylation / physiology*
  • alpha-Synuclein / metabolism*


  • Macromolecular Substances
  • Proteasome Inhibitors
  • SUMO-1 Protein
  • alpha-Synuclein
  • Proteasome Endopeptidase Complex