Publication Date:
2013-10-09
Description:
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 (wt FUS ) or the ALS-associated mutation R521H (mut FUS ) 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 mut FUS or knockdown of fus resulted in impaired motor activity and reduced NMJ synaptic fidelity with reduced quantal transmission. Primary motoneurons expressing mut FUS were found to be more excitable. These impairments in neuronal function could be partially restored in fus AMO larvae also expressing wt FUS ( fus AMO+wt FUS ) but not mut FUS ( fus AMO+mut FUS ). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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