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

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

Journal: Cell reports 2022;39(1):110598

PMID: 35385738

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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 (KIF5A) 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.

Address: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.; Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.; KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.; Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA; George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA; Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA; Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Therapeutic Development Branch, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2022.110598