title: The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.
abstract: The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
authors: Department of Neurology, School of Medicine, Johns Hopkins University.
authors: Ke
authors: K
authors: Zhang
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.
authors: Christopher J
authors: CJ
authors: Donnelly
authors: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University.
authors: Aaron R
authors: AR
authors: Haeusler
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.|Department of Neuroscience, School of Medicine, Johns Hopkins University.
authors: Jonathan C
authors: JC
authors: Grima
authors: Department of Neurology, School of Medicine, Johns Hopkins University.
authors: James B
authors: JB
authors: Machamer
authors: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University.
authors: Peter
authors: P
authors: Steinwald
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.
authors: Elizabeth L
authors: EL
authors: Daley
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.
authors: Sean J
authors: SJ
authors: Miller
authors: Department of Neurology, School of Medicine, Johns Hopkins University.
authors: Kathleen M
authors: KM
authors: Cunningham
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.
authors: Svetlana
authors: S
authors: Vidensky
authors: Department of Neurology, School of Medicine, Johns Hopkins University.
authors: Saksham
authors: S
authors: Gupta
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.
authors: Michael A
authors: MA
authors: Thomas
authors: Department of Neuroscience, School of Medicine, Johns Hopkins University.
authors: Ingie
authors: I
authors: Hong
authors: Department of Neuroscience, School of Medicine, Johns Hopkins University.
authors: Shu-Ling
authors: SL
authors: Chiu
authors: Department of Neuroscience, School of Medicine, Johns Hopkins University.
authors: Richard L
authors: RL
authors: Huganir
authors: Department of Neurology, School of Medicine, Johns Hopkins University.
authors: Lyle W
authors: LW
authors: Ostrow
authors: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University.
authors: Michael J
authors: MJ
authors: Matunis
authors: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University.
authors: Jiou
authors: J
authors: Wang
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.
authors: Rita
authors: R
authors: Sattler
authors: Department of Neurology, School of Medicine, Johns Hopkins University.|Department of Neuroscience, School of Medicine, Johns Hopkins University.
authors: Thomas E
authors: TE
authors: Lloyd
authors: Brain Science Institute, School of Medicine, Johns Hopkins University.|Department of Neuroscience, School of Medicine, Johns Hopkins University.
authors: Jeffrey D
authors: JD
authors: Rothstein
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000073885:C9orf72 Protein; D002467:Cell Nucleus / Q000378:metabolism*; D042622:DNA Repeat Expansion / Q000235:genetics*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology; D054856:G-Quadruplexes; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D022022:Nuclear Pore / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; C092317:RANGAP1 protein, human; C118002:RanGAP protein, Drosophila; D012313:RNA