Neuroscience, Ottawa Hospital Research Institute, Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada, K1H 8M5.
Sci Rep. 2017 Sep 14;7(1):11582. doi: 10.1038/s41598-017-11798-6.
ALS8 is a late-onset familial autosomal dominant form of Amyotrophic Lateral Sclerosis (ALS) caused by a point mutation (P56S) in the VAPB gene (VAMP associated protein isoform B). Here, we generated two C. elegans models of the disease: a transgenic model where human VAPB wild-type (WT) or P56S mutant was expressed in a subset of motor neurons, and a second model that targeted inducible knockdown of the worm's orthologue, vpr-1. Overexpression of human VAPB in DA neurons caused a backward locomotion defect, axonal misguidance, and premature neuronal death. Knockdown of vpr-1 recapitulated the reduction in VAPB expression associated with sporadic cases of human ALS. It also caused backward locomotion defects as well as an uncoordinated phenotype, and age-dependent, progressive motor neuronal death. Furthermore, inhibiting phosphatidylinositol-4 (PtdIns 4)-kinase activity with PIK-93 reduced the incidence of DA motor neuron loss and improved backward locomotion. This supports the loss of VAPB function in ALS8 pathogenesis and suggests that reducing intracellular PtdIns4P might be an effective therapeutic strategy in delaying progressive loss of motor neurons.
ALS8 是一种迟发性家族性常染色体显性形式的肌萎缩侧索硬化症（ALS），由 VAPB 基因（VAMP 相关蛋白同种型 B）中的点突变（P56S）引起。在这里，我们构建了两种疾病的秀丽隐杆线虫模型：一种是在部分运动神经元中表达人源 VAPB 野生型（WT）或 P56S 突变体的转基因模型，另一种是靶向诱导敲低线虫同源物 vpr-1 的模型。在 DA 神经元中过表达人源 VAPB 会导致向后运动缺陷、轴突导向错误和过早的神经元死亡。vpr-1 的敲低重现了与散发性人类 ALS 相关的 VAPB 表达减少。它还导致向后运动缺陷以及不协调表型，并随年龄出现进行性运动神经元死亡。此外，用 PIK-93 抑制磷脂酰肌醇-4（PtdIns4）激酶活性可降低 DA 运动神经元丧失的发生率并改善向后运动。这支持 VAPB 功能丧失在 ALS8 发病机制中的作用，并表明减少细胞内 PtdIns4P 可能是延迟运动神经元进行性丧失的有效治疗策略。
