A cysteine residue affects the conformational state and neuronal toxicity of mutant SOD1 in mice: relevance to the pathogenesis of ALS

作者：Nagano Seiichi; Takahashi Yoko; Yamamoto Kazuhiro; Masutani Hiroshi; Fujiwara Noriko; Urushitani Makoto; Araki Toshiyuki^*

来源：Human Molecular Genetics, 2015, 24(12): 3427-3439.

DOI：10.1093/hmg/ddv093

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.

• 出版日期2015-6-15