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

Richard I Tuxworth, Matthew J Taylor, Ane Martin Anduaga, Alaa Hussien-ali, Sotiroula Chatzimatthaiou, Joanne Longland, Adam M Thompson, Sharif Almutiri, Pavlos Alifragis, Charalambos P Kyriacou, Boris Kysela, Zubair Ahmed

Research output: Contribution to journalArticle

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.
LanguageEnglish
JournalBrain Communications
Early online date2 Jul 2019
DOIs
Publication statusE-pub ahead of print - 2 Jul 2019

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DNA Damage
Neurons
Nervous System Diseases
Nervous System
Nijmegen Breakage Syndrome
Optic Nerve Injuries
Double-Stranded DNA Breaks
Retinal Ganglion Cells
Spinal Ganglia
Neurites
Spinal Cord Injuries
Synapses
Genetic Recombination
Drosophila
Regeneration
Cell Cycle
Stroke
Apoptosis
Pathology

Bibliographical note

© 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.

Cite this

Tuxworth, R. I., Taylor, M. J., Anduaga, A. M., Hussien-ali, A., Chatzimatthaiou, S., Longland, J., ... Ahmed, Z. (2019). Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration.. https://doi.org/10.1093/braincomms/fcz005
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 ; Ahmed, Zubair. / Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration. 2019.
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Tuxworth, RI, Taylor, MJ, Anduaga, AM, Hussien-ali, A, Chatzimatthaiou, S, Longland, J, Thompson, AM, Almutiri, S, Alifragis, P, Kyriacou, CP, Kysela, B & Ahmed, Z 2019, 'Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration'. https://doi.org/10.1093/braincomms/fcz005

Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration. / 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; Ahmed, Zubair.

02.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration

AU - Tuxworth, Richard I

AU - Taylor, Matthew J

AU - Anduaga, Ane Martin

AU - Hussien-ali, Alaa

AU - Chatzimatthaiou, Sotiroula

AU - Longland, Joanne

AU - Thompson, Adam M

AU - Almutiri, Sharif

AU - Alifragis, Pavlos

AU - Kyriacou, Charalambos P

AU - Kysela, Boris

AU - Ahmed, Zubair

N1 - © 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.

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N2 - 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.

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Tuxworth RI, Taylor MJ, Anduaga AM, Hussien-ali A, Chatzimatthaiou S, Longland J et al. Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration. 2019 Jul 2. https://doi.org/10.1093/braincomms/fcz005