title: Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Cystatin C (CysC), an endogenous cysteine protease inhibitor, is a major protein component of Bunina bodies observed in the spinal motor neurons of sporadic ALS and is decreased in the cerebrospinal fluid of ALS patients. Despite prominent deposition of CysC in ALS, the roles of CysC in the central nervous system remain unknown. Here, we identified the neuroprotective activity of CysC against ALS-linked mutant Cu/Zn-superoxide dismutase (SOD1)-mediated toxicity. We found that exogenously added CysC protected neuronal cells including primary cultured motor neurons. Moreover, the neuroprotective property of CysC was dependent on the coordinated activation of two distinct pathways: autophagy induction through AMPK-mTOR pathway and inhibition of cathepsin B. Furthermore, exogenously added CysC was transduced into the cells and aggregated in the cytosol under oxidative stress conditions, implying a relationship between the neuroprotective activity of CysC and Bunina body formation. These data suggest CysC is an endogenous neuroprotective agent and targeting CysC in motor neurons may provide a novel therapeutic strategy for ALS.
authors.affiliation: 1] Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan [2] Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Komaba, Meguro-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hayakawa
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Komaba, Meguro-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Wakasugi
authors.affiliation: 1] Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan [2] Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D055316:Cystatin C / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050505:Mutant Proteins / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000633:toxicity*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D002966:Clathrin; D055316:Cystatin C; D050505:Mutant Proteins; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D013482:Superoxide Dismutase; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D002401:Cathepsin B