TY - JOUR AU - Patten, Shunmoogum A. AU - Aggad, Dina AU - Martinez, Jose AU - Tremblay, Elsa AU - Petrillo, Janet AU - Armstrong, Gary A.B. AU - La Fontaine, Alexandre AU - Maios, Claudia AU - Liao, Meijiang AU - Ciura, Sorana AU - Wen, Xiao-Yan AU - Rafuse, Victor AU - Ichida, Justin AU - Zinman, Lorne AU - Julien, Jean-Pierre AU - Kabashi, Edor AU - Robitaille, Richard AU - Korngut, Lawrence AU - Parker, J. Alexander AU - Drapeau, Pierre T1 - Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis PY - 2017/11/16/ AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.97152 VL - 2 IS - 22 UR - https://doi.org/10.1172/jci.insight.97152 PB - The American Society for Clinical Investigation ER -