SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants

Takako Niikura; Yoshiko Kita; Yoichiro Abe

doi:10.1371/journal.pone.0101080

SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants

PLoS One. 2014 Jun 27;9(6):e101080. doi: 10.1371/journal.pone.0101080. eCollection 2014.

Authors

Takako Niikura¹, Yoshiko Kita², Yoichiro Abe²

Affiliations

¹ Department of Information and Communication Sciences, Faculty of Science and Technology, Sophia University, Tokyo, Japan.
² Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan.

Abstract

Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial amyotrophic lateral sclerosis (ALS), whereby the mutant proteins misfold and aggregate to form intracellular inclusions. We report that both small ubiquitin-like modifier (SUMO) 1 and SUMO2/3 modify ALS-linked SOD1 mutant proteins at lysine 75 in a motoneuronal cell line, the cell type affected in ALS. In these cells, SUMO1 modification occurred on both lysine 75 and lysine 9 of SOD1, and modification of ALS-linked SOD1 mutant proteins by SUMO3, rather than by SUMO1, significantly increased the stability of the proteins and accelerated intracellular aggregate formation. These findings suggest the contribution of sumoylation, particularly by SUMO3, to the protein aggregation process underlying the pathogenesis of ALS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics*
Cell Line, Tumor
HEK293 Cells
Humans
Motor Neurons / metabolism
Mutation*
Protein Aggregation, Pathological / genetics
Protein Aggregation, Pathological / metabolism*
Protein Stability
SUMO-1 Protein / metabolism
Sumoylation
Superoxide Dismutase / genetics*
Superoxide Dismutase / metabolism
Superoxide Dismutase-1
Ubiquitins / metabolism*

Substances

SOD1 protein, human
SUMO-1 Protein
SUMO1 protein, human
SUMO3 protein, human
Ubiquitins
Superoxide Dismutase
Superoxide Dismutase-1

Grants and funding

This work was supported by grants from Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (C) (15590908, http://www.jsps.go.jp) to TN and Keio Gijuku Academic Development funds (no number, http://www.med.keio.ac.jp/research/) to TN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.