ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

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 (KIF5A(Delta Exon27)) 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.

Automated summary

Understanding the pathogenic mechanisms of disease mutations is crucial for advancing treatments. This study found that ALS-associated mutations in the gene encoding microtubule motor KIF5A result in the production of a protein with an abnormal C-terminal sequence, leading to motor activity dysregulation and decreased neuronal survival. These findings shed light on the disruptive effects of pathogenic mutations on intracellular trafficking and neuronal homeostasis.