SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits
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Publication Date
2017-07-05Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Springer Nature
Type
Article
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Whitworth, A., Sanchez-Martinez, A., & Alam, S. M. (2017). SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nature Communications https://doi.org/10.1038/ncomms16063
Abstract
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a
Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of
patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We
further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1
specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of
dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons
and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1
triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded
hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection.
Sponsorship
Medical Research Council (MC_UU_00015/6)
Identifiers
External DOI: https://doi.org/10.1038/ncomms16063
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287050
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