How GGGGCC repeat expansions (REs) in chromosome 9 open reading frame 72 (C9orf72) lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia is unclear. Now, two studies supporting a toxic gain-of-function mechanism add to the debate. Jiang et al. find that C9orf72+/− mice show no overt neuropathology, whereas mice expressing RE-containing C9orf72 show accumulation of RNA foci and behavioural deficits that can be reversed using antisense oligonucleotides against repeat-containing RNAs. Liu et al. generate an RE-containing C9orf72 mouse model that recapitulates the TDP43 (TAR DNA-binding protein 43) inclusions and motor neuron degeneration seen in ALS.
References
Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron http://dx.doi.org/10.1016/j.neuron.2016.04.006 (2016)
Liu, Y. et al. C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron http://dx.doi.org/10.1016/j.neuron.2016.04.005 (2016)
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Bray, N. Repeating mistakes. Nat Rev Neurosci 17, 335 (2016). https://doi.org/10.1038/nrn.2016.64
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DOI: https://doi.org/10.1038/nrn.2016.64
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