Neuromuscular effects of G93A-SOD1 expression in zebrafish.
Neuromuscular effects of G93A-SOD1 expression in zebrafish.
复制标题
DOI：
10.1186/1750-1326-7-44
复制
发表时间：
2012-08-31
影响因子：
15.1
通讯作者：
Feldman EL
中科院分区：
文献类型：
--
作者：
Sakowski SA;Lunn JS;Busta AS;Oh SS;Zamora-Berridi G;Palmer M;Rosenberg AA;Philip SG;Dowling JJ;Feldman EL
肌萎缩侧索硬化症（ALS）是一种涉及运动神经元变性和丧失的致命疾病。ALS运动神经元丢失的机制尚不清楚，也没有有效的治疗方法。远端轴突和神经肌肉接头的缺陷是疾病过程中的早期事件，斑马鱼提供了一个有前途的体内系统来检查ALS发病机制中这些事件的细胞机制和治疗方法。我们证明了斑马鱼表达G93 A-SOD 1（一种与家族性ALS相关的突变）的瞬时遗传操作导致运动神经元生长和轴突分支的早期缺陷。这与先前关于运动神经元轴突缺陷与家族性ALS基因敲除或突变蛋白过表达相关的报道一致。我们还证明了生长因子信号传导的上调能够挽救这些早期缺陷，验证了该模型用于治疗发现的潜力。我们产生了表达G93 A-SOD 1的稳定转基因斑马鱼系，以进一步表征G93 A-SOD 1表达对神经肌肉病理学和疾病进展的影响。行为监测揭示了转基因ALS斑马鱼运动功能障碍和活动减少的证据。在整个疾病过程中，神经肌肉和神经元病理学检查显示，随着疾病进展，神经肌肉接头丢失，运动神经元神经支配模式改变。最后，运动神经元细胞损失在疾病后期明显。这一系列事件反映了ALS中退行性变的逐步机制，并为ALS中神经肌肉退行性变的机制发现和治疗开发提供了新的模型。
Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.
登录
查看更多内容
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
4.5
作者：
Dowling, James J.;Vreede, Andrew P.;Low, Sean E.;Gibbs, Elizabeth M.;Kuwada, John Y.;Bonnemann, Carsten G.;Feldman, Eva L.
通讯作者：
Feldman, Eva L.
影响因子：
4.8
作者：
Jang, Youngmok C.;Lustgarten, Michael S.;Van Remmen, Holly
通讯作者：
Van Remmen, Holly
影响因子：
4.1
作者：
Boulis, NM;Turner, DE;Feldman, EL
通讯作者：
Feldman, EL
影响因子：
9.8
作者：
Chen, YZ;Bennett, CL;Chance, PF
通讯作者：
Chance, PF