@article{ac91cdf69c20489ab9cbdc6664e382f1,
title = "ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function",
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 (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.",
keywords = "ALS, CP: Neuroscience, KIF5A, amyotrophic lateral sclerosis, autoinhibition, axonal transport, kinesin, neurodegenerative disease, neuronal survival",
author = "Baron, {Desiree M.} and Fenton, {Adam R.} and Sara Saez-Atienzar and Anthony Giampetruzzi and Aparna Sreeram and Shankaracharya and Keagle, {Pamela J.} and Doocy, {Victoria R.} and Smith, {Nathan J.} and Danielson, {Eric W.} and Megan Andresano and McCormack, {Mary C.} and Jaqueline Garcia and Val{\'e}rie Bercier and {Van Den Bosch}, Ludo and Brent, {Jonathan R.} and Claudia Fallini and Traynor, {Bryan J.} and Holzbaur, {Erika L.F.} and Landers, {John E.}",
note = "Funding Information: We thank Dr. Michael E. Ward for his generous gift of CYBL1 targeting NIL cassette. We thank Dr. Gelfand for his gift of the Sepharose GFP-Binder Beads. We thank Chris Castaldi and the Yale Center for Genome Analysis for RNA sequencing. We thank Dr. Roshanak Aslebagh and Dr. Scott Shaffer at the UMASS Medical School Mass Spectrometry Facility for sample processing and mass spectrometry analysis. S.S.-A. was supported, in part, by the Intramural Research Program of the NIH , National Institute on Aging ( Z01-AG000949-02 ). V.B. is supported by a postdoctoral fellowship from the FWO -Vlaanderen ( 12Y9120N ). A.G. was supported by a grant from the ALS Association ( 18-PDF-423 ). B.J.T. was supported in part by the Intramural Research Programs of the NIH , National Institute on Aging ( Z01-AG000949-02 ). E.L.F.H. was supported by funding from NIH ( R35 GM126950 ). J.E.L. was supported by funding from NIH / NINDS ( R01NS073873 and R56NS073873 ) and the ALS Association ( 17-SI-386 ). Funding Information: We thank Dr. Michael E. Ward for his generous gift of CYBL1 targeting NIL cassette. We thank Dr. Gelfand for his gift of the Sepharose GFP-Binder Beads. We thank Chris Castaldi and the Yale Center for Genome Analysis for RNA sequencing. We thank Dr. Roshanak Aslebagh and Dr. Scott Shaffer at the UMASS Medical School Mass Spectrometry Facility for sample processing and mass spectrometry analysis. S.S.-A. was supported, in part, by the Intramural Research Program of the NIH, National Institute on Aging (Z01-AG000949-02). V.B. is supported by a postdoctoral fellowship from the FWO-Vlaanderen (12Y9120N). A.G. was supported by a grant from the ALS Association (18-PDF-423). B.J.T. was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02). E.L.F.H. was supported by funding from NIH (R35 GM126950). J.E.L. was supported by funding from NIH/NINDS (R01NS073873 and R56NS073873) and the ALS Association (17-SI-386). Conceptualization, D.M.B. A.R.F. S.S.-A. A.G. A.S. V.B. L.V.D.B. J.R.B. C.F. B.J.T. E.L.F.H. and J.E.L.; methodology, D.M.B. A.R.F. S.S.-A. A.G. N.J.S. J.R.B. C.F. B.J.T. E.L.F.H. and J.E.L.; investigation and validation, D.M.B. A.R.F. A.G. A.S. S. P.J.K. V.R.D. M.A. J.G. J.R.B. and C.F.; formal analysis, D.M.B. A.R.F. A.G. A.S. S. P.J.K. V.R.D. E.W.D. M.A. J.G. J.R.B. and C.F.; software, A.G. S. P.J.K. and E.W.D.; visualization, D.M.B. A.R.F. S.S.-A. A.G. A.S. S. P.J.K. V.R.D. N.J.S. M.A. J.G. J.R.B. and C.F.; writing ? original draft, D.M.B. A.S. V.R.D. M.C.M. and J.E.L.; writing ? review & editing, all authors; resources, M.C.M. S.S.-A. V.B. and L.V.D.B.; funding acquisition, A.G. J.R.B. B.J.T. E.L.F.H. and J.E.L. J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics, a consultant for ACI Clinical LLC sponsored by Biogen, Inc. and Ionis Pharmaceuticals, Inc. J.E.L. is also a consultant for Perkins Coie LLP and may provide expert testimony. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = apr,
day = "5",
doi = "10.1016/j.celrep.2022.110598",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}