Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1196-1202 |
| Number of pages | 7 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 463 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2015 May 26 |
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Keywords
- Amyotrophic lateral sclerosis
- Neurodegenerative diseases
- Protein misfolding
- Superoxide dismutase
- Thiol-disulfide
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Cell Biology
- Molecular Biology
Cite this
Cysteine residues in Cu,Zn-superoxide dismutase are essential to toxicity in Caenorhabditis elegans model of amyotrophic lateral sclerosis. / Ogawa, Mariko; Shidara, Hisashi; Oka, Kotaro; Kurosawa, Masaru; Nukina, Nobuyuki; Furukawa, Yoshiaki.
In: Biochemical and Biophysical Research Communications, Vol. 463, No. 4, 26.05.2015, p. 1196-1202.Research output: Contribution to journal › Article
}
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
PY - 2015/5/26
Y1 - 2015/5/26
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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UR - http://www.scopus.com/inward/citedby.url?scp=84936985866&partnerID=8YFLogxK
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 -