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Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over\u2010activation in hSOD1<jats:sup>G93A<\/jats:sup> transgenic (Tg) mice <jats:italic>in\u00a0vivo<\/jats:italic> by neuron\u2010specific over\u2010expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over\u2010expression of CAST in hSOD1<jats:sup>G93A<\/jats:sup> mice, which lowered calpain activation to levels comparable to wild\u2010type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1<jats:sup>G93A<\/jats:sup>\/CAST mice compared to littermate hSOD1<jats:sup>G93A<\/jats:sup> mice is delayed, which accounts for their longer time of survival. We also find that neuronal over\u2010expression of CAST in hSOD1<jats:sup>G93A<\/jats:sup> transgenic mice inhibited production of\u00a0putative neurotoxic caspase\u2010cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<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\/jnc13536-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\nCAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over\u2010expression of CAST in motor neurons of hSOD1<jats:sup>G93A<\/jats:sup> mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease\u2010causing proteins (TDP\u201043, \u03b1\u2010Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome\u2010mediated cell death mechanisms. Similarly, CAST over\u2010expression in neurons attenuated pathological effects of TDP\u201043, \u03b1\u2010synuclein and Huntingtin. These results suggest a potential value of specific small molecule inhibitors of calpains in delaying the development of ALS.<\/jats:p><jats:p>Read the <jats:bold>Editorial Highlight<\/jats:bold> for this article on page <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/dx.doi.org\/10.1111\/jnc.13296\">140<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13536","type":"journal-article","created":{"date-parts":[[2016,1,12]],"date-time":"2016-01-12T15:08:43Z","timestamp":1452611323000},"page":"253-265","source":"Crossref","is-referenced-by-count":47,"title":["Calpastatin inhibits motor neuron death and increases survival of hSOD1<sup>G93A<\/sup> mice"],"prefix":"10.1111","volume":"137","author":[{"given":"Mala V.","family":"Rao","sequence":"first","affiliation":[{"name":"Nathan S. 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