{Reference Type}: Journal Article
{Title}: ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function.
{Author}: Pant DC;Parameswaran J;Rao L;Loss I;Chilukuri G;Parlato R;Shi L;Glass JD;Bassell GJ;Koch P;Yilmaz R;Weishaupt JH;Gennerich A;Jiang J;
{Journal}: EMBO Rep
{Volume}: 23
{Issue}: 8
{Year}: 08 2022 3
{Factor}: 9.071
{DOI}: 10.15252/embr.202154234
{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.