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

Abstract

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.

How is alpha‐synuclein cleared from the cell?

“…A proportion of Lewy bodies in nigral neurons stain positive for SUMO1 (Rott et al . ), suggesting a role of this modification in Parkinson's pathogenesis. Some studies demonstrated increased α‐Syn aggregation by SUMOylation upon proteasomal inhibition (Kim et al .…”

“…The SUMO ligase PIAS2 promoted SUMOylation of α‐Syn, which in turn reduced α‐Syn ubiquitination by SIAH and NEDD4 ubiquitin ligases and increased aggregation and α‐Syn release from the cells (Rott et al . ). In this context, it was previously shown that SUMOylation utilizes the ESCRT complex to sort α‐Syn into extracellular vesicles for secretion (Kunadt et al .…”

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

“…The protective effect of sumoylation is thought to be due to the enhancement of protein solubility, a finding consistent in studies of many aggregation-prone proteins [94]. In contradiction to these findings, an in vitro study linked sumoylation to impaired α - synuclein ubiquitination and reduced proteasomal degradation [95]. Increased sumoylation was also associated with α-synuclein aggregation in postmortem human brain samples [95].…”

“…In contradiction to these findings, an in vitro study linked sumoylation to impaired α - synuclein ubiquitination and reduced proteasomal degradation [95]. Increased sumoylation was also associated with α-synuclein aggregation in postmortem human brain samples [95]. These contradictory findings highlight the need for further exploration of the role of sumoylation in PD pathogenicity.…”

SUMOylation: One small modification for proteins, multiple giant problems for mankind

“…Rott et al filled this gaping knowledge gap by identifying SUMOylation as a major regulator of α‐synuclein degradation and pathological accumulation. They demonstrated that SUMOylation increases α‐synuclein by 2 mechanisms: (1) α‐synuclein is SUMOylated by PIAS2, which leads to α‐synuclein accumulation, aggregation, and increased levels; and (2) α‐synuclein ubiquitination via SIAH and Nedd4 is blocked, leading to further aggregation.…”