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

Desiree M. Baron, Adam R. Fenton, Sara Saez-Atienzar, Anthony Giampetruzzi, Aparna Sreeram, Shankaracharya, Pamela J. Keagle, Victoria R. Doocy, Nathan J. Smith, Eric W. Danielson, Megan Andresano, Mary C. McCormack, Jaqueline Garcia, Valérie Bercier, Ludo Van Den Bosch, Jonathan R. Brent, Claudia Fallini, Bryan J. Traynor, Erika L.F. Holzbaur, John E. Landers*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) 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.

Original languageEnglish (US)
Article number110598
JournalCell reports
Issue number1
StatePublished - Apr 5 2022


  • ALS
  • CP: Neuroscience
  • KIF5A
  • amyotrophic lateral sclerosis
  • autoinhibition
  • axonal transport
  • kinesin
  • neurodegenerative disease
  • neuronal survival

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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