Pant, D.C., Parameswaran, J., Rao, L., Loss, I., Chilukuri, G., Parlato, R., Shi, L., Glass, J.D., Bassell, G.J., Koch, P., Yilmaz, R., Weishaupt, J.H., Gennerich, A., Jiang, J. (2022). ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function.  EMBO Rep. 23(8): e54234.

FBrf0254225

Research paper

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.

PMC9346498 (PMC) (EuropePMC)