TY - JOUR
T1 - Cysteine residues in Cu,Zn-superoxide dismutase are essential to toxicity in Caenorhabditis elegans model of amyotrophic lateral sclerosis
AU - Ogawa, Mariko
AU - Shidara, Hisashi
AU - Oka, Kotaro
AU - Kurosawa, Masaru
AU - Nukina, Nobuyuki
AU - Furukawa, Yoshiaki
N1 - Funding Information:
We thank Dr. Takuma Sugi for providing a plasmid, pTAK81, for expression of proteins under the control of unc-14 promotor. Wild-type C. elegans strain N2 was provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). This work was supported by Grants-in-Aid 25291028 for Scientific Research (B) and 24111542 and 15H01566 for Scientific Research on Innovative Areas (to Y.F.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan .
Publisher Copyright:
© 2015 Elsevier Inc.All rights reserved.
PY - 2015/7/13
Y1 - 2015/7/13
N2 - Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (ALS). A pathological hallmark of the familial ALS is the formation of mutant SOD1 aggregates, leading to the proposal that SOD1 gains toxicities through protein misfolding triggered by mutations. Nevertheless, molecular requirements for mutant SOD1 to acquire pathogenicity still remain obscure. Here, we show that Cys residues in SOD1 are essential to exerting toxicities of SOD1 in a Caenorhabditis elegans model. Exogenous expression of wild-type as well as pathogenic mutant SOD1 fused with a fluorescent protein in C. elegans resulted in the accumulation of disulfide-reduced SOD1 and retarded the worm's motility. In contrast, little effects of exogenously expressed SOD1 on the motility were observed when all four Cys residues in SOD1 were replaced with Ser. Taken together, we propose that deregulation of Cys chemistry in SOD1 proteins is involved in the pathogenesis of SOD1-related ALS.
AB - Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (ALS). A pathological hallmark of the familial ALS is the formation of mutant SOD1 aggregates, leading to the proposal that SOD1 gains toxicities through protein misfolding triggered by mutations. Nevertheless, molecular requirements for mutant SOD1 to acquire pathogenicity still remain obscure. Here, we show that Cys residues in SOD1 are essential to exerting toxicities of SOD1 in a Caenorhabditis elegans model. Exogenous expression of wild-type as well as pathogenic mutant SOD1 fused with a fluorescent protein in C. elegans resulted in the accumulation of disulfide-reduced SOD1 and retarded the worm's motility. In contrast, little effects of exogenously expressed SOD1 on the motility were observed when all four Cys residues in SOD1 were replaced with Ser. Taken together, we propose that deregulation of Cys chemistry in SOD1 proteins is involved in the pathogenesis of SOD1-related ALS.
KW - Amyotrophic lateral sclerosis
KW - Neurodegenerative diseases
KW - Protein misfolding
KW - Superoxide dismutase
KW - Thiol-disulfide
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U2 - 10.1016/j.bbrc.2015.06.084
DO - 10.1016/j.bbrc.2015.06.084
M3 - Article
C2 - 26086102
AN - SCOPUS:84936985866
VL - 463
SP - 1196
EP - 1202
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -