The C9orf72 repeat expansion disrupts nucleocytoplasmic transport
| Autor: | Michael J. Matunis, Saksham Gupta, Jiou Wang, Elizabeth L. Daley, Richard L. Huganir, Kathleen M. Cunningham, Shu Ling Chiu, Michael A. Thomas, Jeffrey D. Rothstein, Christopher J. Donnelly, Lyle W. Ostrow, Thomas E. Lloyd, Aaron R. Haeusler, Sean J. Miller, Ke Zhang, Svetlana Vidensky, James B. Machamer, Peter Steinwald, Rita Sattler, Jonathan C. Grima, Ingie Hong |
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| Rok vydání: | 2014 |
| Předmět: |
Induced Pluripotent Stem Cells
Active Transport Cell Nucleus Biology Article Open Reading Frames medicine Animals Drosophila Proteins Humans RanGAP Nuclear protein Nuclear export signal Genetics Cell Nucleus Neurons Multidisciplinary DNA Repeat Expansion C9orf72 Protein Neurodegeneration Amyotrophic Lateral Sclerosis GTPase-Activating Proteins Brain Nuclear Proteins Proteins Oligonucleotides Antisense medicine.disease G-Quadruplexes Drosophila melanogaster Nucleocytoplasmic Transport Frontotemporal Dementia Nuclear Pore RNA Female Nuclear transport Trinucleotide repeat expansion |
| Zdroj: | Nature. 525(7567) |
| ISSN: | 1476-4687 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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