PDF(Pubmed)
Abstract：
KIF5A is a kinesin superfamily motor protein that transports various cargos in neurons. Mutations in Kif5a cause familial amyotrophic lateral sclerosis (ALS). These ALS mutations are in the intron of Kif5a and induce mis-splicing of KIF5A mRNA, leading to splicing out of exon 27, which in human KIF5A encodes the cargo-binding tail domain of KIF5A. Therefore, it has been suggested that ALS is caused by loss of function of KIF5A. However, the precise mechanisms regarding how mutations in KIF5A cause ALS remain unclear. Here, we show that an ALS-associated mutant of KIF5A, KIF5A(Δexon27), is predisposed to form oligomers and aggregates in cultured mouse cell lines. Interestingly, purified KIF5A(Δexon27) oligomers showed more active movement on microtubules than wild-type KIF5A in vitro. Purified KIF5A(∆exon27) was prone to form aggregates in vitro. Moreover, KIF5A(Δexon27)-expressing Caenorhabditis elegans neurons showed morphological defects. These data collectively suggest that ALS-associated mutations of KIF5A are toxic gain-of-function mutations rather than simple loss-of-function mutations.
摘要：
KIF5A是驱动蛋白超家族运动蛋白，可在神经元中运输各种货物。Kif5a突变导致家族性肌萎缩侧索硬化(ALS)。这些ALS突变在Kif5a的内含子中，并诱导KIF5AmRNA的错误剪接，导致剪接出外显子27，该外显子在人KIF5A中编码KIF5A的货物结合尾结构域。因此,已经提出ALS是由KIF5A的功能丧失引起的。然而,关于KIF5A突变如何导致ALS的确切机制尚不清楚.这里,我们显示KIF5A的ALS相关突变体，KIF5A(Δexon27),倾向于在培养的小鼠细胞系中形成寡聚体和聚集体。有趣的是,纯化的KIF5A（Δexon27）寡聚体在体外显示出比野生型KIF5A更活跃的微管运动。纯化的KIF5A(Δ外显子27)在体外容易形成聚集体。此外，表达KIF5A（Δexon27）的秀丽隐杆线虫神经元显示形态缺陷。这些数据共同表明，KIF5A的ALS相关突变是毒性功能获得突变，而不是简单的功能丧失突变。
