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Lomerizine, an antagonist of L\u2010 and T\u2010type voltage\u2010gated calcium channels and transient receptor potential channel 5 transient receptor potential channels, is well tolerated clinically, making it a potential therapeutic candidate. Lomerizine reduced glutamate excitotoxicity in cultured motor neurons by reducing the accumulation of cytoplasmic Ca<jats:sup>2+<\/jats:sup> and protected motor neurons against multiple measures of mutant <jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>1 toxicity: Ca<jats:sup>2+<\/jats:sup> overload, impaired mitochondrial trafficking, mitochondrial fragmentation, formation of mutant <jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>1 inclusions, and loss of viability. To assess the utility of lomerizine in other forms of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>, calcium homeostasis was evaluated in culture models of disease because of mutations in the <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010binding proteins transactive response <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\u2010binding protein 43 (<jats:styled-content style=\"fixed-case\">TDP<\/jats:styled-content>\u201043) and Fused in Sarcoma (<jats:styled-content style=\"fixed-case\">FUS<\/jats:styled-content>). Calcium did not play the same role in the toxicity of these mutant proteins as with mutant <jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>1 and lomerizine failed to prevent cytoplasmic accumulation of mutant <jats:styled-content style=\"fixed-case\">TDP<\/jats:styled-content>\u201043, a hallmark of its pathology. These experiments point to differences in the pathogenic pathways between types of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> and show the utility of primary culture models in comparing those mechanisms and effectiveness of therapeutic strategies.\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\/jnc12738-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Calcium sensitivity is a factor in motor neuron vulnerability in ALS. The voltage\u2010gated calcium channel blocker lomerizine normalized [Ca<jats:sup>2+<\/jats:sup>] and reduced toxicity of mutant Cu\/Zn\u2010superoxide dismutase (SOD1) causing familial ALS1. Calcium homeostasis was not disrupted in motor neurons expressing ALS\u2010associated mutants of TAR DNA\u2010binding protein 43 (TDP\u201043) or FUS, nor was lomerizine protective, affirming differences in pathogenic mechanism and therapeutic efficacy in the forms of ALS.\n<\/jats:p>","DOI":"10.1111\/jnc.12738","type":"journal-article","created":{"date-parts":[[2014,4,9]],"date-time":"2014-04-09T13:07:53Z","timestamp":1397048873000},"page":"455-466","source":"Crossref","is-referenced-by-count":18,"title":["The voltage\u2010gated calcium channel blocker lomerizine is neuroprotective in motor neurons expressing mutant <scp>SOD<\/scp>1, but not <scp>TDP<\/scp>\u201043"],"prefix":"10.1111","volume":"130","author":[{"given":"Luan T.","family":"Tran","sequence":"first","affiliation":[{"name":"Department of Neurology\/Neurosurgery Montreal Neurological Institute McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit J.","family":"Gentil","sequence":"additional","affiliation":[{"name":"Department of Neurology\/Neurosurgery Montreal Neurological Institute McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen E.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Neurology\/Neurosurgery Montreal Neurological Institute McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather D.","family":"Durham","sequence":"additional","affiliation":[{"name":"Department of Neurology\/Neurosurgery Montreal Neurological Institute McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,5,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurt.2008.08.002"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(93)91620-8"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410360608"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.08.031"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.093"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4003-12.2013"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1248\/yakushi1947.115.2_120"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.06.017"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00582.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199403033300901"},{"key":"e_1_2_7_12_1","doi-asserted-by":"crossref","first-page":"7722","DOI":"10.1523\/JNEUROSCI.18-19-07727.1998","article-title":"Rapid Ca2+ entry through Ca2\n                  +\u00a0\u2010permeable AMPA\/kainate channesl triggers marked intracellular Ca2+ rises and consequent oxygen radical production","volume":"18","author":"Carriedo S. 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