GENETICS OF NERVOUS SYSTEM DISEASESCalpastatin reduces toxicity of SOD1G93A in a culture model of amyotrophic lateral sclerosisTradewell, Miranda L.; Durham, Heather D.Author Information Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada Correspondence to Heather D. Durham PhD, Department of Neurology and Neurosurgery, Montreal Neurological Institute, 3801 University Street, Room 649, Montreal, QC H3A 2B4, Canada Tel: +1 514 398 8508; fax: +1 514 398 1509; e-mail: [email protected] Received 25 May 2010 accepted 4 July 2010 NeuroReport: October 27, 2010 - Volume 21 - Issue 15 - p 976-979 doi: 10.1097/WNR.0b013e32833ddd45 Buy Metrics 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 (SOD1G93A) 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 SOD1G93A in motor neurons of dissociated spinal cord cultures, prolonging viability of and reducing the proportion containing SOD1G93A inclusions. The data support the central role of calcium dysregulation in ALS and identify a potential therapeutic pathway. © 2010 Lippincott Williams & Wilkins, Inc.