Other Biochemistry, Biophysics, and Structural Biology Commons^™

Als-Associated Kif5a Mutations Abolish Autoinhibition Resulting In A Toxic Gain Of Function, Desiree M. Barron, 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, Brian J. Traynor, Erica L.F. Holzbaur, John E. Landers

Biochemistry -- Faculty Publications

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 …