ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function
Devesh C. Pant,Janani Parameswaran,Lu Rao,Isabel Loss,Ganesh Chilukuri,Rosanna Parlato,Liang Shi,Jonathan D. Glass,Gary J. Bassell,Philip Koch,Rustem Yilmaz,Jochen H. Weishaupt,Arne Gennerich,Jie Jiang +13 more
TLDR
Results suggest gain of function as an underlying disease mechanism in KIF5A-associated ALS and the mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules.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 ΔExon27). However, the underlying pathogenic mechanism is still unknown. In this study, we performed 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.read more
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Journal ArticleDOI
ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function
Devesh C. Pant,Janani Parameswaran,Lu Rao,Isabel Loss,Ganesh Chilukuri,Rosanna Parlato,Liang Shi,Jonathan D. Glass,Gary J. Bassell,Philip Koch,Rustem Yilmaz,Jochen H. Weishaupt,Arne Gennerich,Jie Jiang +13 more
TL;DR: Results suggest gain of function as an underlying disease mechanism in KIF5A-associated ALS and the mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules.
Journal ArticleDOI
An ALS‐associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity
TL;DR: It is shown that an ALS-associated mutant of Kif5A, KIF5A(Δexon27), is predisposed to form oligomers and aggregates in cultured mouse cell lines, and these data collectively suggest that ALS- associated mutations of K IF5A are toxic gain-of-function mutations rather than simple loss-of -function mutations.
Journal ArticleDOI
Molecular architecture of the autoinhibited kinesin-1 lambda particle
TL;DR: In this paper , the coiled-coil architecture of heterotetrameric kinesin-1 was revealed by combining computational structure prediction with single-particle negative-stain electron microscopy.
Posted ContentDOI
Molecular architecture of the autoinhibited kinesin-1 lambda particle
Johannes F. Weijman,Sathish K. N. Yadav,Katherine J Surridge,Jessica A. Cross,Ufuk Borucu,Judith Mantell,Derek N. Woolfson,Christiane Schaffitzel,Mark P. Dodding +8 more
TL;DR: Integration of computational structure prediction with electron microscopy reveals the coiled-coil architecture of the autoinhibited compact conformer of the microtubule motor, kinesin-1.
Journal ArticleDOI
Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport
Rongde Qiu,Junhu Zhang,Xin Xiang +2 more
TL;DR: While dynein activation involves dynactin, cargo adapter and LIS1, this study adds kinesin-1 autoinhibition as a new regulatory factor in vivo to promote Dynein cargo initiation in a way mechanistically distinct from LIS2-promoted dyne in switching from its autoinhibited form.
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