ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function
Desiree M. Baron, Adam R. Fenton, Sara Sáez-Atiénzar, Anthony Giampetruzzi, Aparna Sreeram, Shankaracharya, Pamela Keagle, Victoria R. Doocy, Nathan J. Smith, Eric 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
Abstract
) 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.