Non-SUMOylated alternative spliced isoforms of alpha-synuclein are more aggregation-prone and toxic

Mech Ageing Dev. 2023 Jan:209:111759. doi: 10.1016/j.mad.2022.111759. Epub 2022 Dec 2.

Abstract

The exon skipping of α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD), forms four isoforms. In contrast to the full length α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. SUMOylation, a post-translational modification, regulates α-Syn function, aggregation, and degradation, but information about α-Syn isoforms and the effect of SUMOylation on them is unknown. Therefore, this study aims to characterize the SUMOylation of α-Syn isoforms and its impact on cell death and α-Syn aggregation. In a cellular model of PD induced by rotenone, cell toxicity, SUMOylation, and α-Syn aggregation with or without isoforms overexpression were evaluated. First, rotenone induced cell toxicity and α-Syn aggregation, with a significant reduction of SUMOylation and autophagy. Boosting SUMOylation prevented α-Syn aggregation, phosphorylation and recovery of autophagy. Moreover, α-Syn 140 and α-Syn 126 were SUMOylated while the other two isoforms, α-Syn 112 and 98 were not and their overexpression showed that were more toxic and induced more α-Syn aggregation. Rotenone increased their toxicity that was not affected by boosting SUMOylation. These results may indicate a role of SUMOylation in modulating α-Syn aggregation, inducing to understanding more about the behavior of α-Syn isoforms.

Keywords: Apoptosis; Autophagy; Parkinson's Disease; SUMOylation; α-Synuclein Splicing Isoforms.

MeSH terms

  • Humans
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Rotenone / toxicity
  • Sumoylation
  • alpha-Synuclein* / genetics

Substances

  • alpha-Synuclein
  • Rotenone
  • Protein Isoforms