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Cell Rep. 2013 Dec 12;5(5):1178-86. doi: 10.1016/j.celrep.2013.10.049. Epub 2013 Nov 27.

Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic.

Author information

1
Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London SE5 8AF, UK.
2
MRC Centre for Developmental Neurobiology, London SE1 1UL, UK.
3
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
4
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
5
Department of Neuroscience, King's College London, Institute of Psychiatry, London SE5 8AF, UK.
6
Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London SE5 8AF, UK; Department of Public Health, Neuroscience, Experimental, and Forensic Medicine, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
7
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
8
Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London SE5 8AF, UK. Electronic address: christopher.shaw@kcl.ac.uk.

Abstract

The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intranuclear neuronal RNA foci have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 38× and 72× G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.

PMID:
24290757
PMCID:
PMC3898469
DOI:
10.1016/j.celrep.2013.10.049
[Indexed for MEDLINE]
Free PMC Article

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