Sumoylation inhibits α-synuclein aggregation and toxicity

• DOI: 10.1083/jcb.201010117
• Publication Date: 2011-07-11T17:00:04Z
• Authors: Petranka Krumova; Erik Meulmeester; Manuel Garrido; Marilyn Tirard; He-Hsuan Hsiao; Guillaume Bossis; Henning Urlaub; Markus Zweckstetter; Sebastian Kügler; Frauke Melchior; Mathias Bähr; Jochen H. Weishaupt
• Keywords: Neurons; 0301 basic medicine; 0303 health sciences; Dopamine; Sumoylation; Apoptosis; Mice, Transgenic; Recombinant Proteins; Cell Line; Substantia Nigra; Kinetics; Mice; 03 medical and health sciences; Solubility; Mutation; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Small Ubiquitin-Related Modifier Proteins; alpha-Synuclein; Animals; Humans; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Research Articles

Posttranslational modification of proteins by attachment small ubiquitin-related modifier (SUMO) contributes to numerous cellular phenomena. Sumoylation sometimes creates and abolishes binding interfaces, but increasing evidence points another role for sumoylation in promoting the solubility aggregation-prone proteins. Using purified α-synuclein, an protein implicated Parkinson’s disease that was previously reported be sumoylated upon overexpression, we compared aggregation kinetics unmodified modified α-synuclein. Whereas α-synuclein formed fibrils, remained soluble. The presence as little 10% sufficient delay significantly vitro. We mapped SUMO acceptor sites showed simultaneous mutation lysines 96 102 arginine impaired vitro cells. Importantly, this double mutant increased propensity cytotoxicity a cell-based assay dopaminergic neurons substantia nigra vivo. These findings strongly support model promotes suggest defects may contribute aggregation-induced diseases.