The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Authors

Ke Zhang, Department of Neurology, 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, Department of Neurology, 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, Department of Neurology, School of Medicine, Johns Hopkins University.
Svetlana Vidensky, Brain Science Institute, School of Medicine, Johns Hopkins University.
Saksham Gupta, Department of Neurology, School of Medicine, Johns Hopkins University.
Michael A. Thomas, Brain Science Institute, School of Medicine, Johns Hopkins University.
Ingie Hong, Department of Neuroscience, School of Medicine, Johns Hopkins University.
Shu-Ling Chiu, Department of Neuroscience, School of Medicine, Johns Hopkins University.
Richard L. Huganir, Department of Neuroscience, School of Medicine, Johns Hopkins University.
Lyle W. Ostrow, Department of Neurology, 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, Department of Neurology, School of Medicine, Johns Hopkins University.
Jeffrey D. Rothstein, Brain Science Institute, School of Medicine, Johns Hopkins University.

Document Type

Article

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.

Medical Subject Headings

Active Transport, Cell Nucleus (genetics); Amyotrophic Lateral Sclerosis (genetics, pathology); Animals; Brain (metabolism, pathology); C9orf72 Protein; Cell Nucleus (metabolism); DNA Repeat Expansion (genetics); Drosophila Proteins (metabolism); Drosophila melanogaster (cytology, metabolism); Female; Frontotemporal Dementia (genetics, pathology); G-Quadruplexes; GTPase-Activating Proteins (metabolism); Humans; Induced Pluripotent Stem Cells (cytology, metabolism); Neurons (metabolism, pathology); Nuclear Pore (chemistry, metabolism); Nuclear Proteins (metabolism); Oligonucleotides, Antisense (genetics); Open Reading Frames (genetics); Proteins (genetics); RNA (genetics, metabolism)

Publication Date

9-3-2015

Publication Title

Nature

E-ISSN

1476-4687

Volume

525

Issue

7567

First Page

56

Last Page

61

PubMed ID

26308891

Digital Object Identifier (DOI)

10.1038/nature14973

Recommended Citation

Zhang, Ke; Donnelly, Christopher J.; Haeusler, Aaron R.; Grima, Jonathan C.; Machamer, James B.; Steinwald, Peter; Daley, Elizabeth L.; Miller, Sean J.; Cunningham, Kathleen M.; Vidensky, Svetlana; Gupta, Saksham; Thomas, Michael A.; Hong, Ingie; Chiu, Shu-Ling; Huganir, Richard L.; Ostrow, Lyle W.; Matunis, Michael J.; Wang, Jiou; Sattler, Rita; Lloyd, Thomas E.; and Rothstein, Jeffrey D., "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport" (2015). Translational Neuroscience. 1377.
https://scholar.barrowneuro.org/neurobiology/1377