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
Affiliations
Desiree M. Baron
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Adam R. Fenton
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
Sara Saez-Atienzar
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA
Anthony Giampetruzzi
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Aparna Sreeram
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Shankaracharya
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Pamela J. Keagle
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Victoria R. Doocy
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Nathan J. Smith
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
Eric W. Danielson
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Megan Andresano
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Mary C. McCormack
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jaqueline Garcia
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Valérie Bercier
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
Ludo Van Den Bosch
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
Jonathan R. Brent
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Claudia Fallini
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
Bryan J. Traynor
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
Erika L.F. Holzbaur
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
John E. Landers
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author
Summary: 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.
