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Neuroprotection, Neurotoxicity and Neuroinflammation

開催日 2014/9/13
時間 16:00 - 17:00
会場 Room I(311+312)
Chairperson(s) 丸山 和佳子 / Wakako Maruyama (独立行政法人国立長寿医療研究センター 加齢健康脳科学研究部 / Department of Cognitive Brain Science, National Center for Geriatries and Gerontology, Japan)
澤田 誠 / Makoto Sawada (名古屋大学 環境医学研究所 / Research Institute of Environmental Medicine, Nagoya University, Japan)

Neuroprotective mechanisms of cystatin C against mutant SOD1-mediated toxicity

  • O3-I-4-3
  • 渡邊 征爾 / Seiji Watanabe:1 若杉 桂輔 / Keisuke Wakasugi:2 山中 宏二 / Koji Yamanaka:1 
  • 1:名古屋大環境医病態神経 / Dept Neurosci Pathobiol, RIEM, Nagoya Univ, Aichi, Japan 2:東京大院総合文化研生命環境科学 / Dept Life Sci, Grad Sch of Arts and Sci, Univ of Tokyo, Tokyo, Japan 

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by a selective loss of motor neurons. Mutations in SOD1 gene are the most frequent causes of familial ALS. Cystatin C (CysC), an endogenous cysteine protease inhibitor, is a major protein component of Bunina bodies in sporadic ALS and decreased in the patients' cerebrospinal fluid. Despite the prominent deposition of CysC in ALS, the role of CysC had not been clarified. In this study, we examined the potential neuroprotective activity of CysC against mutant SOD1-mediated toxicity. We found that exogenously added recombinant CysC protected neuronal cells including primary cultured motor neurons. The neuroprotective activity of CysC was dependent on coordinated activation of two distinct neuroprotective pathways: induction of autophagy through AMP-activated kinase and inhibition of aberrantly activated cathepsin B. Moreover, CysC, which was transduced into lysosomes under normal conditions, was leaked into cytosol and aggregated under oxidative stress conditions, implying the relationship between the neuroprotective activity of CysC and Bunina body formation. These data suggest that CysC is an endogenous neuroprotective agent and might be a novel promising therapeutic target for ALS.

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