ZFIN ID: ZDB-PUB-190726-6
The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis
Bose, P., Tremblay, E., Maois, C., Narasimhan, V., Armstrong, G.A.B., Liao, M., Parker, J.A., Robitaille, R., Wen, X.Y., Barden, C., Drapeau, P.
Date: 2019
Source: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics   16(4): 1149-1166 (Journal)
Registered Authors: Drapeau, Pierre, Wen, Xiao-Yan
Keywords: ALS, C. elegans, C9ORF72, Mice, Motorneuron, NMJ, SOD-1, TDP-43, Therapeutics, Zebrafish
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/drug therapy*
  • Amyotrophic Lateral Sclerosis/genetics*
  • Amyotrophic Lateral Sclerosis/metabolism
  • Animals
  • Animals, Genetically Modified
  • C9orf72 Protein/genetics*
  • Caenorhabditis elegans
  • DNA-Binding Proteins/administration & dosage
  • DNA-Binding Proteins/metabolism
  • Disease Models, Animal*
  • Humans
  • Locomotion/drug effects
  • Locomotion/physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuromuscular Junction/drug effects
  • Neuromuscular Junction/genetics*
  • Neuromuscular Junction/metabolism
  • Organ Culture Techniques
  • Pimozide/administration & dosage
  • Pimozide/metabolism
  • Superoxide Dismutase-1/genetics*
  • Zebrafish
PubMed: 31342410 Full text @ Neurotherapeutics
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of pimozide, a recently identified repurposed neuroleptic for ALS, in Caenorhabditis elegans, confirmed the hits in zebrafish and validated the most active compounds in mouse genetic models. Out of the 27 small molecules identified from the high-throughput screen in worms, 4 were found to recover locomotor defects in C. elegans and genetic zebrafish models of ALS. TRVA242 was identified as the most potent compound as it significantly improved efficiency in rescuing locomotor, motorneuron, and neuromuscular junction synaptic deficits in a C. elegans TDP-43 model and in multiple zebrafish genetic (TDP-43, SOD1, and C9ORF72) models of ALS. The actions of TRVA242 were also conserved in a mammalian model as it also stabilized neuromuscular junction deficits in a mouse SOD1 model of ALS. Compounds such as TRVA242 therefore represent new potential therapeutics for the treatment of ALS.