Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration

Abstract

DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. 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 Aβ1-42-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.

Publication DOI: https://doi.org/10.1093/braincomms/fcz005
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
Additional Information: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Funding: UK Biotechnology and Biological Sciences Research Council New Investigator award BB/N008472/1, Marie-Curie ITN grant INsecTIME PITN-GA- 2012-316790 (C.P.K), Saudi Education Ministry PhD Studentship, University of Birmingham Bryant Bequest PhD Studentship and a UK Medical Research Council Confidence in Concept award.
Full Text Link:
Related URLs: https://academi ... /fcz005/5526876 (Publisher URL)
PURE Output Type: Article
Published Date: 2019-07-02
Accepted Date: 2019-06-19
Authors: Tuxworth, Richard I
Taylor, Matthew J
Anduaga, Ane Martin
Hussien-ali, Alaa
Chatzimatthaiou, Sotiroula
Longland, Joanne
Thompson, Adam M
Almutiri, Sharif
Alifragis, Pavlos
Kyriacou, Charalambos P
Kysela, Boris (ORCID Profile 0000-0002-1096-6816)
Ahmed, Zubair

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