ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function

Pant, D.; Parameswaran, J.; Rao, L.; Shi, L.; Chilukuri, G.; McEachin, Z.; Glass, J.; Bassell, G. J.; Gennerich, A.; Jiang, J.

doi:10.1101/2022.03.05.483071

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bioRxiv · 10.1101/2022.03.05.483071

ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function

Pant, D.·Parameswaran, J.·Rao, L.·Shi, L.·Chilukuri, G.·McEachin, Z.·Glass, J.·Bassell, G. J.·Gennerich, A.·Jiang, J.

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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 produce motor proteins with an altered C-terminal tail (referred to as {Delta}Exon27). However, the underlying pathogenic mechanism is still unknown. In this study, we performed a comprehensive analysis of {Delta}Exon27 at the single-molecule, cellular, and organism levels. Our results show that {Delta}Exon27 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 {Delta}Exon27 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.

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Pant, D., Parameswaran, J., Rao, L., Shi, L., Chilukuri, G., McEachin, Z., Glass, J., Bassell, G. J., Gennerich, A., Jiang, J.. 2022-03-07. ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function. https://doi.org/10.1101/2022.03.05.483071

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