期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 12, 页码 3427-3439出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv093
关键词
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资金
- Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP [22590932, 25461302]
- Takeda Science Foundation
- Pfizer
- Grants-in-Aid for Scientific Research [26290023, 22590932, 25460386, 25461302] Funding Source: KAKEN
We previously showed by in vitro experiments that the cysteine residue (Cys111) near the dimer interface is critical for monomerization and resultant aggregate formation of mutant Cu, Zn-superoxide dismutase (SOD1) protein, which is toxic to motor neurons in familial amyotrophic lateral sclerosis (ALS). To verify the importance of Cys111 in the mutant SOD1-associated ALS pathogenesis in vivo, we analyzed the disease phenotype of SOD1 transgenic mice harboring H46R mutation alone (H46R mice) or H46R/C111S double mutations (H46R/C111S mice). Behavioral, histological and biochemical analyses of the spinal cord showed that the onset and progression of the disease phenotype were delayed in H46R/C111S mice compared with H46R mice. We found that peroxidized Cys111 of H46R SOD1 plays a role in promoting formation of high molecular weight insoluble SOD1 species that is correlated with the progression of the motor neuron disease phenotype. These results support that Cys111 is a critical residue for the neuronal toxicity of mutant SOD1 in vivo, and the blockage of peroxidation of this residue in mutant SOD1 may constitute a future target for developing ALS treatment.
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