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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: Pant, Devesh C. (Author) , Parameswaran, Janani (Author) , Rao, Lu (Author) , Loss, Isabel (Author) , Chilukuri, Ganesh (Author) , Parlato, Rosanna (Author) , Shi, Liang (Author) , Glass, Jonathan D (Author) , Bassell, Gary J (Author) , Koch, Philipp (Author) , Yılmaz, Rüstem (Author) , Weishaupt, Jochen H. (Author) , Gennerich, Arne (Author) , Jiang, Jie (Author)
Format: Article (Journal)
Language:English
Published: 23 June 2022
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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Summary: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.
Item Description:Im Titel ist "Delta" bei DeltaExon27 mit einem griechischen Buchstaben geschrieben
Gesehen am 30.10.2023
Physical Description:Online Resource
ISSN:1469-3178
DOI:10.15252/embr.202154234

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