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

Abstract Background: To date, four alternative splicing isoforms arising from exon skipping have been identified for α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD). In contrast to the full length,140 amino acid α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. Small ubiquitin-like modification, SUMOylation, is a post-translational modification that regulates α-Syn function, aggregation, and degradation. There is limited information about α-Syn isoforms, their SUMOylation, and whether SUMOylation modulates these proteins' activity and fate. Therefore, this study has aimed to characterize the SUMOylation of α-Syn isoforms and its impact on cell death and α-Syn aggregation. Results: In a cellular model of PD induced by rotenone, cell toxicity, SUMOylation, and α-Syn aggregation with or without isoforms overexpression were evaluated in SH-SY5Y cells. First, we found that rotenone induced cell toxicity and α-Syn aggregation, associated with a significant reduction of SUMOylation and autophagy. Interestingly, boosting the SUMOylation machinery by overexpressing SUMO-1 prevented the α-Syn aggregation and phosphorylation and recovered the autophagy activity. The findings also revealed that α-Syn 140 and α-Syn 126 (lacks exon 3) were SUMOylated while the other two isoforms, α-Syn 112 and 98, arise from exon 3 and exon 3, 5 skipping respectively were not. Moreover, overexpressing the isoforms showed that those lacking exon 5 were more toxic and induced more α-Syn aggregation. Their toxicity was exacerbated in the presence of rotenone and was not affected by boosting the SUMOylation. Conclusions: These results show that the non-SUMOylated isoforms of α-Syn are more toxic and they may shed light on the role of SUMOylation machinery in modulating α-Syn aggregation also as pharmacological target and may set the stage for understanding more about the behavior of α-Syn isoforms.