Biochemistry, Department of

 

Date of this Version

4-4-2022

Citation

Cell Reports 39, 110598, April 5, 2022

doi:10.1016/j.celrep.2022.110598

Comments

Copyright © 2022 The Author(s). This is an open access article under the CC BY-NC-ND license

Abstract

Understandingthepathogenicmechanismsof diseasemutations is critical toadvancingtreatments.ALS-associated mutations in the gene encoding the microtubulemotor KIF5A result in skipping of exon 27 (KIF5ADExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore,mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.

Baron CR 2022 ALS-associated KIF5A--NIH MS.pdf (2937 kB)
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