The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis
| Autor: | Gary A. B. Armstrong, Poulomee Bose, Christopher Barden, Claudia Maios, J. Alex Parker, Vijay Narasimhan, Richard Robitaille, Xiao-Yan Wen, Meijiang Liao, Elsa Tremblay, Pierre Drapeau |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Neurology SOD1 Neuromuscular Junction Mice Transgenic Biology Neuromuscular junction Animals Genetically Modified Mice 03 medical and health sciences Organ Culture Techniques Superoxide Dismutase-1 0302 clinical medicine C9orf72 Genetic model medicine Animals Humans Pharmacology (medical) Amyotrophic lateral sclerosis Caenorhabditis elegans Zebrafish Pharmacology C9orf72 Protein Amyotrophic Lateral Sclerosis Pimozide Correction biology.organism_classification medicine.disease DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Original Article Neurology (clinical) Neuroscience Locomotion 030217 neurology & neurosurgery |
| Zdroj: | Neurotherapeutics |
| Popis: | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00765-w) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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