Human Polycomb protein 2 promotes alpha-synuclein aggregate formation through covalent SUMOylation

Abstract

Parkinson's disease (PD) manifests from the impairment of motor systems due to the specific loss of dopaminergic neurons and the appearance of intracellular filamentous inclusions called Lewy bodies (LBs). alpha-Synuclein, a major component of LBs, is known to contribute to the pathogenesis of PD. Although alpha-synuclein is known to be a target of diverse posttranslational modifications, the contribution of alpha-synuclein SUMOylation and its functional consequences have not yet been fully characterized. Here, we demonstrate that human Polycomb protein 2 (hPc2) binds to alpha-synuclein and may function as a SUMO E3 ligase to promote the SUMOylation of alpha-synuclein. In addition, hPc2 promotes the SUMOylation of alpha-synuclein in the presence of MG-132-induced proteasome inhibition, which consequently promotes alpha-synuclein aggregate formation. Furthermore, the increased formation of intracellular alpha-synuclein aggregates, which predominantly contain SUMOylated alpha-synuclein, significantly reduces the death of fibroblast cells in response to staurosporine. In summary, the results from this study demonstrate that the hPc2-induced SUMOylation of alpha-synuclein could function as a cytoprotector by increasing alpha-synuclein aggregate formation within fibroblast cells.