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.