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

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

doi:10.1093/braincomms/fcz005

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.

Highlights

DNA double-strand breaks are the most deleterious type of DNA damage
Activation and recruitment of ataxia telangiectasia mutated (ATM) to the site of double-strand breaks lead to multiple phosphorylation events, one of which is the phosphorylation of histone cis the histone H2Ax (cH2Ax) at and around the site of the break, resulting in the formation of characteristic cH2Axþ nuclear foci (Shrivastav et al, 2008)
The mean sensing and removal time (Supplementary Fig. 4F) and mean ratio of slips to total steps (Supplementary Fig. 4G) in the sensory and locomotor tests were improved, with animals being indistinguishable from sham-treated animals by 3 weeks, when compared with mirin and KU-60019 treatment. These results demonstrate that knockdown of Mre11 and ATM as well as mirin and KU-60019 treatment to inhibit the DNA damage response is functionally beneficial after spinal cord injury (SCI)

Summary

Introduction

Doublestrand breaks trigger the DNA damage response to arrest the cell cycle in and mount repair via non-homologous end-joining in G1 or G2 phases or homologous recombination in M and S phases (Mladenov et al, 2016). Unrepaired double-strand breaks in neurons lead to persistent activation of the DNA damage response which, in turn, is a trigger for dysregulation of the cell cycle and aberrant re-entry of neurons into G1 leading to neural dysfunction, apoptosis and senescence (Herrup et al, 2004). Association of the MRN complex to double-strand breaks leads to recruitment and activation of the ataxia telangiectasia mutated (ATM) kinase, which coordinates multiple arms of the DNA damage response, including cell-cycle arrest, repair and apoptosis (Shiloh and Ziv, 2013). Double-strand breaks are characterized by the activation of sensor kinases, including DNA-protein

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Conclusion