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.
Footnotes
Abbreviations AD = Alzheimer’s disease; ATM = ataxia telangiectasia mutated; ATR = ataxia telangiectasia and Radiation 3-related protein; BSA = bovine serum albumin; cAMP = cyclic adenosine monophosphate; CAP = compound action potential; CME = CNS myelin extracts; CMV = cytomegalovirus; CNTF = ciliary neurotrophic factor; Cy3 = cyanine 3; DAPI = 4’,6-diamidino-2-phenylindole; DC = dorsal column; DMEM = Dulbecco’s modified Eagle’s medium; DMSO = dimethyl sulfoxide; DN1 = dorsal neuron 1; DN2 = dorsal neuron 2; DRG = dorsal root ganglion; DRGN = dorsal root ganglion neurons; FBS = foetal bovine serum; FGF2 = fibroblast growth factor 2; GAP43 = growth associated protein 43; GLMM = generalised linear mixed models; HD = Huntington’s disease; HRP = horseradish peroxidase; IC50 = half maximum inhibitory concentration; IgG = Immunoglobulin; lLNv = large lateral neuron ventral; LMM = linear mixed models; LNd = lateral neuron dorsal; Mre11 = meiotic recombination 11; MRN complex = meiotic recombination 11/Radiation 50/Nijmegen breakage syndrome 1 complex; Nbs1 = Nijmegen breakage syndrome 1; NF = neurofilament; ONC = optic nerve crush; PAGE = polyacrylamide gel electrophoresis; PBS = phosphate buffered saline; PDF = pigment dispersing factor; PFA = paraformaldehyde; P/S = penicillin/streptomycin; PTEN = phosphatase and tensin homolog; RGC = retinal ganglion cells; Rad50 = Radiation 50; RT = room temperature; SCI = spinal cord injury; SDS = sodium dodecyl sulphate; shRNA = short hairpin RNA; siCASP2 = short interfering RNA to caspase-2; sLNv = small lateral neuron ventral; TBS = Tris buffered saline; UAS = upstream activation sequence.
Axon regeneration data in the optic system and spinal cord has been included in figures 4 and 6. Figure 1D was removed.