title: Mutant Huntingtin Disrupts the Nuclear Pore Complex.
abstract: Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Grima
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: J Gavin
authors.initials: JG
authors.lastname: Daigle
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Arbez
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Cunningham
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ochaba
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Charlene
authors.initials: C
authors.lastname: Geater
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Morozko
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stocksdale
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jenna C
authors.initials: JC
authors.lastname: Glatzer
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Pham
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ishrat
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Harsh
authors.initials: H
authors.lastname: Wadhwa
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: Center for NeuroGenetics, Departments of Molecular Genetics and Microbiology and Neurology, College of Medicine, Genetics Institute, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Laura P W
authors.initials: LPW
authors.lastname: Ranum
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lloyd
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jrothstein@jhmi.edu.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics*; D057026:Induced Pluripotent Stem Cells; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D022022:Nuclear Pore / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D029721:Drosophila Proteins; C086055:HTT protein, human; C542005:Htt protein, Drosophila; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D028861:Nuclear Pore Complex Proteins
keywords: C9ORF72; Huntington’s disease; KPT-350; O-GlcNAc; RAN translation; Thiamet-G; induced pluripotent stem cell; neurodegeneration; nuclear pore complex; nucleocytoplasmic transport