Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1‐linked amyotrophic lateral sclerosis mice
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- Seiji Watanabe
- Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine Nagoya University Chikusa‐ku Aichi Japan
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- Okiru Komine
- Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine Nagoya University Chikusa‐ku Aichi Japan
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- Fumito Endo
- Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine Nagoya University Chikusa‐ku Aichi Japan
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- Keisuke Wakasugi
- Department of Life Sciences Graduate School of Arts and Sciences The University of Tokyo, Komaba Meguro‐ku Tokyo Japan
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- Koji Yamanaka
- Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine Nagoya University Chikusa‐ku Aichi Japan
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<jats:title>Abstract</jats:title><jats:sec><jats:label/><jats:p>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 <jats:italic>SOD1</jats:italic> 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 <jats:italic>in vitro</jats:italic>; however, <jats:italic>in vivo</jats:italic> evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC <jats:italic>in vivo</jats:italic> using a mouse model of ALS in which the ALS‐linked mutated SOD1 gene is expressed (SOD1<jats:sup>G93A</jats:sup> mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1<jats:sup>G93A</jats:sup> 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‐1α, 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.</jats:p></jats:sec><jats:sec><jats:label/><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc14285-fig-0007-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p></jats:sec>
収録刊行物
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- Journal of Neurochemistry
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Journal of Neurochemistry 145 (1), 80-89, 2018-02-07
Wiley