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

doi:10.1016/j.celrep.2022.110598

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

Cell Rep. 2022 Apr 5;39(1):110598. doi: 10.1016/j.celrep.2022.110598.

Authors

Desiree M Baron¹, Adam R Fenton², Sara Saez-Atienzar³, Anthony Giampetruzzi¹, Aparna Sreeram¹, Shankaracharya¹, Pamela J Keagle¹, Victoria R Doocy¹, Nathan J Smith⁴, Eric W Danielson¹, Megan Andresano¹, Mary C McCormack¹, Jaqueline Garcia¹, Valérie Bercier⁵, Ludo Van Den Bosch⁵, Jonathan R Brent⁶, Claudia Fallini⁷, Bryan J Traynor⁸, Erika L F Holzbaur², John E Landers⁹

Affiliations

¹ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
² 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.
³ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
⁴ Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
⁵ 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.
⁶ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁷ 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.
⁸ 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.
⁹ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: john.landers@umassmed.edu.

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^ΔExon27) 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.

Keywords: ALS; CP: Neuroscience; KIF5A; amyotrophic lateral sclerosis; autoinhibition; axonal transport; kinesin; neurodegenerative disease; neuronal survival.

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Axonal Transport / genetics
Gain of Function Mutation
Humans
Kinesins / genetics
Mutation / genetics

Substances

KIF5A protein, human
Kinesins

Abstract

MeSH terms

Substances

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