title: Calpastatin reduces toxicity of SOD1G93A in a culture model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset, rapidly progressing, fatal disease occurring in both familial and sporadic forms. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) cause ALS through a gain of toxic function. Calpain activity is increased in mutant SOD1 (SOD1(G93A)) transgenic mice and in models of ischemia because of increased cytosolic calcium, which has been documented in motor neurons in rodent models of familial ALS and in sporadic ALS patients. We report that inhibition of calpain activity using calpastatin prevented the toxicity of SOD1(G93A) in motor neurons of dissociated spinal cord cultures, prolonging viability of and reducing the proportion containing SOD1(G93A) inclusions. The data support the central role of calcium dysregulation in ALS and identify a potential therapeutic pathway.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Tradewell
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors; D002449:Cell Aggregation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; C033668:calpastatin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D002154:Calpain