title: Sumoylation inhibits alpha-synuclein aggregation and toxicity.
abstract: Posttranslational modification of proteins by attachment of small ubiquitin-related modifier (SUMO) contributes to numerous cellular phenomena. Sumoylation sometimes creates and abolishes binding interfaces, but increasing evidence points to another role for sumoylation in promoting the solubility of aggregation-prone proteins. Using purified α-synuclein, an aggregation-prone protein implicated in Parkinson's disease that was previously reported to be sumoylated upon overexpression, we compared the aggregation kinetics of unmodified and modified α-synuclein. Whereas unmodified α-synuclein formed fibrils, modified α-synuclein remained soluble. The presence of as little as 10% sumoylated α-synuclein was sufficient to delay aggregation significantly in vitro. We mapped SUMO acceptor sites in α-synuclein and showed that simultaneous mutation of lysines 96 and 102 to arginine significantly impaired α-synuclein sumoylation in vitro and in cells. Importantly, this double mutant showed increased propensity for aggregation and cytotoxicity in a cell-based assay and increased cytotoxicity in dopaminergic neurons of the substantia nigra in vivo. These findings strongly support the model that sumoylation promotes protein solubility and suggest that defects in sumoylation may contribute to aggregation-induced diseases.
authors: Department of Neurology and 2 Department of Biochemistry I, University of Göttingen, 37073 Göttingen, Germany.
authors: Petranka
authors: P
authors: Krumova
authors: Erik
authors: E
authors: Meulmeester
authors: Manuel
authors: M
authors: Garrido
authors: Marilyn
authors: M
authors: Tirard
authors: He-Hsuan
authors: HH
authors: Hsiao
authors: Guillaume
authors: G
authors: Bossis
authors: Henning
authors: H
authors: Urlaub
authors: Markus
authors: M
authors: Zweckstetter
authors: Sebastian
authors: S
authors: Kügler
authors: Frauke
authors: F
authors: Melchior
authors: Mathias
authors: M
authors: Bähr
authors: Jochen H
authors: JH
authors: Weishaupt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D012995:Solubility; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D058207:Sumoylation / Q000502:physiology*; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity
chemical_list: D011994:Recombinant Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D051844:alpha-Synuclein; D004298:Dopamine