Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1-linked amyotrophic lateral sclerosis mice.
JOURNAL OF NEUROCHEMISTRY(2018)
摘要
Cystatin C (CysC) is a major protein component of Bunina bodies, which are a pathological hallmark observed in the remaining motor neurons of patients with amyotrophic lateral sclerosis (ALS). Dominant mutations in the SOD1 gene, encoding Cu/Zn superoxide dismutase (SOD1), are causative for a subset of inherited ALS cases. Our previous study showed that CysC exerts a neuroprotective effect against mutant SOD1-mediated toxicity invitro; however, invivo evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC invivo using a mouse model of ALS in which the ALS-linked mutated SOD1 gene is expressed (SOD1(G93A) mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1(G93A) mice extended their survival times. Administered CysC was predominantly distributed in ventral horn neurons including motor neurons, and induced autophagy through AMP-activated kinase activation to reduce the amount of insoluble mutant SOD1 species. Moreover, PGC-1, a disease modifier of ALS, was restored by CysC through AMP-activated kinase activation. Finally, the administration of CysC also promoted aggregation of CysC in motor neurons, which is similar to Bunina bodies. Taken together, our findings suggest that CysC represents a promising therapeutic candidate for ALS.
更多查看译文
关键词
Amyotrophic lateral sclerosis (ALS),Cu/Zn superoxide dismutase (SOD1),Cystatin C (CysC),AMP-activated kinase (AMPK)
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络