%0 Journal Article
%T ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function.
%A Pant DC
%A Parameswaran J
%A Rao L
%A Loss I
%A Chilukuri G
%A Parlato R
%A Shi L
%A Glass JD
%A Bassell GJ
%A Koch P
%A Yilmaz R
%A Weishaupt JH
%A Gennerich A
%A Jiang J
%J EMBO Rep
%V 23
%N 8
%D 08 2022 3
%M 35735139
%F 9.071
%R 10.15252/embr.202154234
%X 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.