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Persistent activation of the DNA damage response in response to double-strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the DNA damage response by targeting the meiotic recombination 11, Rad50, Nijmegen breakage syndrome 1 complex, which is involved in double-strand break recognition, is neuroprotective in three neurodegeneration models in Drosophila and prevents A\u03b21-42-induced loss of synapses in embryonic hippocampal neurons. Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. We conclude that muting the DNA damage response in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.<\/jats:p>","DOI":"10.1093\/braincomms\/fcz005","type":"journal-article","created":{"date-parts":[[2019,7,2]],"date-time":"2019-07-02T01:52:41Z","timestamp":1562032361000},"source":"Crossref","is-referenced-by-count":32,"title":["Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration"],"prefix":"10.1093","volume":"1","author":[{"given":"Richard I","family":"Tuxworth","sequence":"first","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3055-4453","authenticated-orcid":false,"given":"Matthew J","family":"Taylor","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane","family":"Martin Anduaga","sequence":"additional","affiliation":[{"name":"Department of Genetics & Genome Biology, University of Leicester, Leicester LE1 7RH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Hussien-Ali","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Science, Centre of Gene and Cell Therapy, School of Biological Sciences, Royal Holloway University of London, Surrey TW20 0EX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sotiroula","family":"Chatzimatthaiou","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Longland","sequence":"additional","affiliation":[{"name":"Neuroscience and Ophthalmology, College of Medical and Dental Sciences, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M","family":"Thompson","sequence":"additional","affiliation":[{"name":"Neuroscience and Ophthalmology, College of Medical and Dental Sciences, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharif","family":"Almutiri","sequence":"additional","affiliation":[{"name":"Neuroscience and Ophthalmology, College of Medical and Dental Sciences, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"},{"name":"Applied Medical Science College, Shaqra University, Addawadmi, Riyadh, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlos","family":"Alifragis","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Science, Centre of Gene and Cell Therapy, School of Biological 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