ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Authors

Desiree M. Barron, University of Massachusetts Medical School
Adam R. Fenton, University of Pennsylvania Perelman School of Medicine
Sara Saez-Atienzar, National Institute on Aging, NIH
Anthony Giampetruzzi, University of Massachusetts Medical School
Aparna Sreeram, University of Massachusetts Medical School
Shankaracharya, University of Massachusetts Medical School
Pamela J. Keagle, University of Massachusetts Medical School
Victoria R. Doocy, University of Massachusetts Medical School
Nathan J. Smith, University of Nebraska-LincolnFollow
Eric W. Danielson, University of Massachusetts Medical School
Megan Andresano, University of Massachusetts Medical School
Mary C. McCormack, University of Massachusetts Medical School
Jaqueline Garcia, University of Massachusetts Medical School
Valérie Bercier, University of Leuven
Ludo Van Den Bosch, University of Leuven
Jonathan R. Brent, Feinberg School of Medicine, Northwestern University
Claudia Fallini, University of Massachusetts Medical School
Brian J. Traynor, National Institute on Aging, NIH
Erica L.F. Holzbaur, University of Pennsylvania Perelman School of Medicine
John E. Landers, University of Massachusetts Medical SchoolFollow

Document Type

Article

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.