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Neuron. 2016 May 4;90(3):535-50. doi: 10.1016/j.neuron.2016.04.006. Epub 2016 Apr 21.

Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.

Author information

1
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
2
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
4
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
5
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
6
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Physiology, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore.
7
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
8
Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; Neuroregeneration Laboratory, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
9
Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; Neuroregeneration Laboratory, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 9, 04001 Kosice, Slovakia.
10
Laboratory of Neurobiology, Vesalius Research Center, Experimental Neurology, Department of Neurosciences, KU Leuven/VIB, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
11
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
12
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
13
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
14
German Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians University and Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen Strasse 17, 81377 Munich, Germany.
15
Institute of Psychiatry, King's College London, London WC2R 2LS, UK.
16
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dcleveland@ucsd.edu.
17
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: clagier-tourenne@mgh.harvard.edu.

Abstract

Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.

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