SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation

Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13176-13181. doi: 10.1073/pnas.1704351114. Epub 2017 Nov 27.


α-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in α-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases α-synuclein levels by relieving the inhibition exerted on α-synuclein proteasomal degradation. α-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated α-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of α-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of α-synuclein by PIAS2 promotes α-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on α-synuclein. Second, SUMOylation facilitates α-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of α-synuclein SUMOylation provide a strategy to reduce α-synuclein levels and possibly aggregation in PD.

Keywords: Parkinson’s disease; SUMOylation; aggregation; ubiquitination; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Neurons / drug effects
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / metabolism
  • Proteolysis*
  • Rats, Sprague-Dawley
  • Salicylates / pharmacology
  • Substantia Nigra / metabolism
  • Sumoylation*
  • alpha-Synuclein / metabolism*


  • PIAS2 protein, human
  • Protein Inhibitors of Activated STAT
  • Salicylates
  • alpha-Synuclein
  • ginkgolic acid