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

Cell Reports (Apr 2022)

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

Journal volume & issue: Vol. 39, no. 1
p. 110598

Abstract

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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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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