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JCI Insight. 2017 Nov 16;2(22). pii: 97152. doi: 10.1172/jci.insight.97152. eCollection 2017 Nov 16.

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.

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Department of Neuroscience, Université de Montréal, Montréal, Canada.
Centre de recherche du centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
INRS Institut Armand-Frappier, Laval, Canada.
Institut des Biomolécules Max Mousseron IBMM, UMR 5247, CNRS-Université Montpellier-ENSCM, Montpellier, France.
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Alberta, Canada.
FRQS Groupe de recherche sur le système nerveux central, Montreal, Canada.
Department of Neurology and Neurosurgery, McGill University and Montreal Neurological Institute, Montreal, Canada.
Sorbonne Université, Université Pierre et Marie Curie (UPMC), Université de Paris 06, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.
Zebrafish Centre for Advanced Drug Discovery & Keenan Research Centre for Biomedical Science, Li Ka Sheng Knowledge Institute, St. Michael's Hospital and Department of Medicine & Physiology, University of Toronto, Toronto, Ontario, Canada.
Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine and Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, California, USA.
Department of Neurology, University of Toronto, Sunnybrook Health Sciences Centre,Toronto, Ontario, Canada.
Centre de recherche CERVO, Chemin de la Canardière, Université Laval, Québec City, Canada.


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.


ALS; Calcium channels; Clinical Trials; Neurodegeneration; Neuroscience

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