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Updated: Sep 27, 2025

Aip1p Dynamics Are Altered by the R256H Mutation in Actin
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ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Desiree M Baron1, Adam R Fenton2, Sara Saez-Atienzar3

  • 1Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Cell Reports
|April 6, 2022
PubMed

Insights

Amyotrophic lateral sclerosis (ALS) mutations in KIF5A cause a toxic gain of function, leading to disrupted motor activity, axonal transport, and neuronal death. This research clarifies the pathogenic mechanisms of KIF5A mutations in ALS.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Understanding pathogenic mechanisms of disease mutations is crucial for developing effective treatments.
  • Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons.

Purpose of the Study:

  • To investigate the functional consequences of ALS-associated KIF5A mutations.
  • To elucidate the pathogenic mechanisms underlying KIF5A-linked ALS.

Main Methods:

  • Expression of ALS-linked mutant KIF5A (KIF5AΔExon27).
  • Single-molecule analysis of motor activity.
  • Assessment of cellular mislocalization, axonal transport, and neuronal survival.
  • Analysis of protein-RNA interactions and gene expression/splicing.

Main Results:

  • ALS-linked KIF5A mutations lead to dysregulated motor activity and altered axonal transport.
  • Mutant KIF5A exhibits a constitutively active state due to its altered C terminus.
  • Expression of mutant KIF5A results in altered protein/RNA interactions and gene expression.
  • Decreased neuronal survival was observed in the presence of mutant KIF5A.

Conclusions:

  • ALS-associated KIF5A mutations confer a toxic gain of function.
  • Mutant KIF5A disrupts intracellular trafficking and neuronal homeostasis, contributing to ALS pathogenesis.
Keywords:
ALSCP: NeuroscienceKIF5Aamyotrophic lateral sclerosisautoinhibitionaxonal transportkinesinneurodegenerative diseaseneuronal survival

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