ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function
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 ?Exo...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
23 June 2022
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| In: |
EMBO reports
Year: 2022, Volume: 23, Issue: 8, Pages: 1-18 |
| ISSN: | 1469-3178 |
| DOI: | 10.15252/embr.202154234 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.15252/embr.202154234 Verlag, kostenfrei, Volltext: http://www.embopress.org/doi/full/10.15252/embr.202154234 
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| Author Notes: | Devesh C Pant, Janani Parameswaran, Lu Rao, Isabel Loss, Ganesh Chilukuri, Rosanna Parlato, Liang Shi, Jonathan D Glass, Gary J Bassell, Philipp Koch, Rüstem Yilmaz, Jochen H Weishaupt, Arne Gennerich and Jie Jiang |
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| 245 | 1 | 0 | |a ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function |c Devesh C Pant, Janani Parameswaran, Lu Rao, Isabel Loss, Ganesh Chilukuri, Rosanna Parlato, Liang Shi, Jonathan D Glass, Gary J Bassell, Philipp Koch, Rüstem Yilmaz, Jochen H Weishaupt, Arne Gennerich and Jie Jiang |
| 246 | 3 | 3 | |a ALS-linked KIF5A DeltaExon27 mutant causes neuronal toxicity through gain-of-function |
| 264 | 1 | |c 23 June 2022 | |
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| 520 | |a 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 ?Exon27). 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 ?Exon27 at the single-molecule, cellular, and organism levels. Our results show that ?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 ?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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