Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS
Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS
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DOI：
10.1093/hmg/ddt278
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发表时间：
2013-11-01
影响因子：
3.5
通讯作者：
Drapeau, Pierre
中科院分区：
文献类型：
--
作者：
Armstrong, Gary A. B.;Drapeau, Pierre
肌萎缩性侧索硬化症（ALS）临床表现于成年期，其特征是脊髓和大脑皮层运动神经元的丧失。该疾病的动物模型表明，在该疾病的临床前阶段存在显著的神经元异常。肉瘤融合基因（FUS）突变与ALS相关，并在动物模型中引起运动功能损伤。然而，神经肌肉功能障碍的机制尚不清楚，其潜在的病理生理缺陷导致的运动功能损伤是由突变的FUS表达引起的。为了表征细胞病理生理缺陷，我们在斑马鱼幼鱼中表达了野生型人类基因（wtFUS）或als相关突变R521H （mutFUS）基因，并表征了它们的运动（游泳）活性和神经肌肉连接（NMJs）功能。此外，我们用反义morpholino oligonucleotide （fus AMO）检测了斑马鱼fus的敲除。表达mutFUS或敲低fus都会导致运动活动受损，NMJ突触保真度降低，量子传递减少。表达mutFUS的初级运动神经元更易兴奋。这些神经元功能损伤在表达wtFUS （fus AMOwtFUS）而不表达mutFUS （fus AMOmutFUS）的fus AMO幼虫中可以部分恢复。这些结果表明，FUS功能的丧失和获得都会导致NMJ突触前功能的缺陷。
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 AMOwtFUS) but not mutFUS (fus AMOmutFUS). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ.