ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function

ABSTRACT: 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. Further, mutant KIF5A possesses novel 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Desiree Baron  

LAB HEAD: John Edward Landers

PROVIDER: PXD031012 | Pride | 2022-06-09

REPOSITORIES: Pride