title: C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins.
abstract: Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Department of Neurology, School of Medicine, Johns Hopkins University, Maryland, USA.|Brain Science Institute, School of Medicine, Johns Hopkins University, Maryland, USA.|Department of Neuroscience, School of Medicine, Johns Hopkins University, Maryland, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Grima
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Katzman
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Melissa E
authors.identifier: http://orcid.org/0000-0001-7379-2545
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Aliesha
authors.initials: A
authors.lastname: Garrett
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Stankowski
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Daughrity
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Jimei
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Perkerson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Yue
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chew
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Aishe
authors.initials: A
authors.lastname: Kurti
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Zizhao S
authors.initials: ZS
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Liesinger
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Baker
authors.affiliation: Ludwig Institute, University of California at San Diego, La Jolla, California, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Institute for Metabolic Biochemistry, Ludwig Maximilians University Munich, Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Dieter
authors.identifier: http://orcid.org/0000-0002-7186-4653
authors.initials: D
authors.lastname: Edbauer
authors.affiliation: Ludwig Institute, University of California at San Diego, La Jolla, California, USA.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Integrative Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Link
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.affiliation: Department of Neurology, School of Medicine, Johns Hopkins University, Maryland, USA.|Brain Science Institute, School of Medicine, Johns Hopkins University, Maryland, USA.|Department of Neuroscience, School of Medicine, Johns Hopkins University, Maryland, USA.
authors.forename: Jeffrey D
authors.identifier: http://orcid.org/0000-0003-2001-8470
authors.initials: JD
authors.lastname: Rothstein
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Dennis W
authors.identifier: http://orcid.org/0000-0001-7189-7917
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000073885:C9orf72 Protein; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D061251:Primary Cell Culture; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D057149:Ubiquitinated Proteins; C000606498:C9orf72 protein, mouse; C475578:Rad23a protein, mouse; C499250:Rad23b protein, mouse; C578077:Tardbp protein, mouse; C501002:Xpc protein, mouse; C000622116:poly(glycyl-alanyl)