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ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function.
- Source :
-
EMBO reports [EMBO Rep] 2022 Aug 03; Vol. 23 (8), pp. e54234. Date of Electronic Publication: 2022 Jun 23. - Publication Year :
- 2022
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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 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.<br /> (© 2022 The Authors.)
Details
- Language :
- English
- ISSN :
- 1469-3178
- Volume :
- 23
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- EMBO reports
- Publication Type :
- Academic Journal
- Accession number :
- 35735139
- Full Text :
- https://doi.org/10.15252/embr.202154234