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

Pant, Devesh C; Parameswaran, Janani; Rao, Lu; Shi, Liang; Chilukuri, Ganesh; McEachin, Zachary T.; Glass, Jonathan D.; Bassell, Gary J.; Gennerich, Arne; Jiang, Jie

doi:10.1101/2022.03.05.483071

Cited by 9 publications

(16 citation statements)

References 46 publications

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“…Our data suggest that the ∆exon27 mutation in KIF5A induces toxic aggregates. Furthermore, while we were preparing this manuscript, a preprint supporting the same conclusion was posted on Biorxiv (Pant et al, 2022). The study showed that KIF5A(∆exon27) causes aggregate formation in cultured cells and is toxic when expressed in Drosophila .…”

Section: Discussionmentioning

confidence: 89%

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An ALS‐associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

2022

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KIF5A is a kinesin superfamily motor protein that transports various cargos in neurons. Mutations in Kif5a cause familial amyotrophic lateral sclerosis (ALS).These ALS mutations are in the intron of Kif5a and induce mis-splicing of KIF5A mRNA, leading to splicing out of exon 27, which in human KIF5A encodes the cargo-binding tail domain of KIF5A. Therefore, it has been suggested that ALS is caused by loss of function of KIF5A. However, the precise mechanisms regarding how mutations in KIF5A cause ALS remain unclear.Here, we show that an ALS-associated mutant of KIF5A, KIF5A(Δexon27), is predisposed to form oligomers and aggregates in cultured mouse cell lines. Interestingly, purified KIF5A(Δexon27) oligomers showed more active movement on microtubules than wild-type KIF5A in vitro. Purified KIF5A(Δexon27) was prone to form aggregates in vitro. Moreover, KIF5A(Δexon27)-expressing Caenorhabditis elegans neurons showed morphological defects. These data collectively suggest that ALS-associated mutations of KIF5A are toxic gain-offunction mutations rather than simple loss-of-function mutations.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 92%

An ALS‐associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

2022

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“…Our data suggest that the Δexon27 mutation in KIF5A induces toxic aggregates. Furthermore, while we were preparing this manuscript, a preprint supporting the same conclusion was posted on Biorxiv (Pant et al, 2022). The study showed that KIF5A(Δexon27) causes aggregate formation in cultured cells and is toxic when expressed in Drosophila .…”

Section: Discussionmentioning

confidence: 91%

“…Our data suggest Δexon27 mutation in KIF5A induces toxic aggregations. While we are preparing this manuscript, a preprint showing similar results has been posted on Biorxiv (Pant et al, 2022). They show unpurified KIF5A(Δexon27) in cell lysates is more active than wild type KIF5A; however, it remained elusive KIF5A(Δexon27) by itself is hyperactive or KIF5A(Δexon27) is activated by binding with unidentified factors.…”

Section: Discussionmentioning

confidence: 99%

An ALS-associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

Nakano

Chiba

Niwa

2022

Preprint

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KIF5A is a kinesin superfamily motor protein that transport various cargos in neurons. Mutations in Kif5a cause familial amyotrophic lateral sclerosis (ALS). These ALS mutations are in the intron of Kif5a and induce missplicing of KIF5A mRNA, leading to splicing out of exon 27. Exon 27 of KIF5A encodes a cargo-binding tail domain of KIF5A; therefore, it has been suggested ALS is caused by loss of function of KIF5A. However, precise mechanisms how mutations in KIF5A cause ALS remain to be clarified. Here, we show that the ALS-associated mutant of KIF5A, KIF5A(Δexon27), is predisposed to form oligomers and aggregations in vivo and in vitro. Interestingly, KIF5A(Δexon27) oligomers moved on microtubules more actively than wild type KIF5A in vitro. Moreover, KIF5A(Δexon27)-expressed worm neurons showed morphological defects. These data collectively suggest that ALS-associated mutations of KIF5A are toxic gain of function, rather than a simple loss of function.

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“…Alternatively, given that mutations in the tail and motor domain of KIF22 both disrupt chromosome segregation, the tail and motor domain may interact to inactivate the motor. Head-tail autoinhibition is a known regulatory mechanism of other members of the kinesin superfamily (Blasius et al, 2021; Coy, Hancock, Wagenbach, & Howard, 1999; Espeut et al, 2008; Friedman & Vale, 1999; Hammond, Blasius, Soppina, Cai, & Verhey, 2010; Hammond et al, 2009; Imanishi, Endres, Gennerich, & Vale, 2006; Ren et al, 2018; Verhey & Hammond, 2009; Verhey et al, 1998), and disruption of autoinhibition can be a mechanism of disease pathogenesis (Asselin et al, 2020; Bianchi et al, 2016; Blasius et al, 2021; Cheng et al, 2014; Pant et al, 2022; van der Vaart et al, 2013). Mutations in either the tail or motor domain could disrupt this interaction, preventing KIF22 inactivation in anaphase.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Thompson

Blackburn

Babovic‐Vuksanovic

et al. 2021

Preprint

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The chromokinesin KIF22 uses plus end-directed motility and direct binding to chromosome arms to generate pushing forces that contribute to mitotic chromosome congression and alignment. Mutations in the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the coiled-coil domain of the KIF22 tail. The mechanism by which these mutations affect development is unknown. We assessed whether pathogenic mutations affect the function of KIF22 in mitosis and demonstrate that mutations do not result in a loss of KIF22 function. Pathogenic mutations did not alter the localization or prometaphase function of KIF22. Instead, mutations disrupted chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, a phosphomimetic mutation, which constitutively activates the motor, phenocopied the effects of pathogenic mutations. These findings offer insight into the mechanism by which mutations in KIF22 may affect human development, the balance between polar ejection forces and antiparallel microtubule sliding in anaphase, and potential mechanisms of KIF22 regulation.

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

Cited by 9 publications

References 46 publications

An ALS‐associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

An ALS‐associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

An ALS-associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

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