PDF(Pubmed)
Abstract：
Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and are predicted to produce motor proteins with an altered C-terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. Here, we confirm the expression of KIF5A mutant proteins in patient iPSC-derived motor neurons. We perform a comprehensive analysis of ΔExon27 at the single-molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis, and premature death. Our results suggest gain-of-function as an underlying disease mechanism in KIF5A-associated ALS.
摘要：
人类驱动蛋白家族成员5A（KIF5A）基因的突变最近被确定为肌萎缩侧索硬化症（ALS）的遗传原因。几种KIF5AALS变体引起外显子27跳跃，并预测产生具有改变的C末端尾部的运动蛋白（称为ΔExon27）。然而,潜在的致病机制仍然未知。这里,我们证实了KIF5A突变蛋白在患者iPSC来源的运动神经元中的表达。我们对单分子进行了ΔExon27的综合分析，细胞，和有机体水平。我们的结果表明，ΔExon27易于形成细胞质聚集体，并且具有神经毒性。突变缓解了运动自抑制，增加了运动自联想，导致微管的持续合成能力大大增强。最后,黑腹果蝇中ΔExon27的异位表达会导致机翼缺损，运动障碍,瘫痪过早死亡。我们的结果表明，功能获得是KIF5A相关ALS的潜在疾病机制。
