Oxidative modification of cysteine 111 promotes disulfide bond-independent aggregation of SOD1.
Converging evidence indicates that SOD1 aggregation is a common feature of mutant SOD1-linked fALS, and seems to be directly related to the gain-of-function toxic property. However, the mechanism inducing the aggregation is not understood. To study the contribution of oxidative modification of cysteine residues in SOD1 aggregation, we systematically examined the redox state of SOD1 cysteine residues in the G37R transgenic mouse model at different stages of the disease and under oxidative stress induced by H₂O₂. Our data suggest that under normal circumstance, cysteine 111 residue in SOD1 is free; however, under oxidative stress, it is prone to oxidative modification by providing the thiolate anion (S-). With the progression of the disease, increased levels of oxidative insults facilitated the oxidation of thiol groups of cysteine residues; human mutant SOD1 could generate an upper shift band in reducing SDS-PAGE, which turned out to be a Cys111-peroxidized SOD1 species. We also detected the formation of SOD1 multimers at different stages of the disease, and found that accumulated oxidative stress facilitated the formation of aggregates, which were not mediated by disulfide bond. This oxidative modification of cysteine 111 therefore promotes the formation of disulfide bond-independent aggregation of SOD1.
Department of Human Anatomy and Cell Science, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada.
Xueping
X
Chen
Huifang
H
Shang
Xiaozhong
X
Qiu
Noriko
N
Fujiwara
Liying
L
Cui
Xin-Min
XM
Li
Tian-Ming
TM
Gao
Jiming
J
Kong
D000818:Animals; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D016716:PC12 Cells; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D004220:Disulfides; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003545:Cysteine