PDF(Pubmed)
Abstract：
Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.
摘要：
了解疾病突变的致病机制对于推进治疗至关重要。编码微管运动KIF5A的基因中的ALS相关突变导致外显子27（KIF5AΔExon27）的跳跃，并编码具有新的39个氨基酸残基C末端序列的蛋白质。这里,我们报道，ALS相关突变体KIF5A的表达导致运动活动失调，细胞定位错误,改变轴突运输，并降低了神经元的存活率。单分子分析显示,突变体KIF5A的改变的C末端导致组成型活性状态。此外，突变型KIF5A具有改变的蛋白质和RNA相互作用,并且其表达导致改变的基因表达/剪接。一起来看,我们的数据支持以下假设:致病性ALS突变导致细胞内运动KIF5A的毒性功能增加,破坏细胞内运输和神经元稳态.
