title: Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) presents clinically in adulthood and is characterized by the loss of motoneurons in the spinal cord and cerebral cortex. Animal models of the disease suggest that significant neuronal abnormalities exist during preclinical stages of the disease. Mutations in the gene fused in sarcoma (FUS) are associated with ALS and cause impairment in motor function in animal models. However, the mechanism of neuromuscular dysfunction underlying pathophysiological deficits causing impairment in locomotor function resulting from mutant FUS expression is unknown. To characterize the cellular pathophysiological defect, we expressed the wild-type human gene (wtFUS) or the ALS-associated mutation R521H (mutFUS) gene in zebrafish larvae and characterized their motor (swimming) activity and function of their neuromuscular junctions (NMJs). Additionally, we tested knockdown of zebrafish fus with an antisense morpholino oligonucleotide (fus AMO). Expression of either mutFUS or knockdown of fus resulted in impaired motor activity and reduced NMJ synaptic fidelity with reduced quantal transmission. Primary motoneurons expressing mutFUS were found to be more excitable. These impairments in neuronal function could be partially restored in fus AMO larvae also expressing wtFUS (fus AMO+wtFUS) but not mutFUS (fus AMO+mutFUS). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ.
authors.affiliation: Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, QC, Canada H3C 3J7.
authors.forename: Gary A B
authors.initials: GA
authors.lastname: Armstrong
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D009043:Motor Activity; D009046:Motor Neurons / Q000502:physiology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology*; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism*; D013550:Swimming / Q000502:physiology; D009435:Synaptic Transmission; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D034702:RNA-Binding Protein FUS; D029961:Zebrafish Proteins