The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Ke Zhang, Christopher J. Donnelly, Aaron R. Haeusler, Jonathan C. Grima, James B. Machamer, Peter Steinwald, Elizabeth L. Daley, Sean J. Miller, Kathleen M. Cunningham, Svetlana Vidensky, Saksham Gupta, Michael A. Thomas, Ingie Hong, Shu-Ling Chiu, Richard L. Huganir, Lyle W. Ostrow, Michael J. Matunis, Jiou Wang, Rita Sattler, Thomas E. Lloyd () and Jeffrey D. Rothstein ()
Additional contact information
Ke Zhang: School of Medicine, Johns Hopkins University
Christopher J. Donnelly: Brain Science Institute, School of Medicine, Johns Hopkins University
Aaron R. Haeusler: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University
Jonathan C. Grima: Brain Science Institute, School of Medicine, Johns Hopkins University
James B. Machamer: School of Medicine, Johns Hopkins University
Peter Steinwald: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University
Elizabeth L. Daley: Brain Science Institute, School of Medicine, Johns Hopkins University
Sean J. Miller: Brain Science Institute, School of Medicine, Johns Hopkins University
Kathleen M. Cunningham: School of Medicine, Johns Hopkins University
Svetlana Vidensky: Brain Science Institute, School of Medicine, Johns Hopkins University
Saksham Gupta: School of Medicine, Johns Hopkins University
Michael A. Thomas: Brain Science Institute, School of Medicine, Johns Hopkins University
Ingie Hong: School of Medicine, Johns Hopkins University
Shu-Ling Chiu: School of Medicine, Johns Hopkins University
Richard L. Huganir: School of Medicine, Johns Hopkins University
Lyle W. Ostrow: School of Medicine, Johns Hopkins University
Michael J. Matunis: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University
Jiou Wang: Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University
Rita Sattler: Brain Science Institute, School of Medicine, Johns Hopkins University
Thomas E. Lloyd: School of Medicine, Johns Hopkins University
Jeffrey D. Rothstein: Brain Science Institute, School of Medicine, Johns Hopkins University

Nature, 2015, vol. 525, issue 7567, 56-61

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14973

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