Abstract
DNA double strand breaks feature in neurological disorders, including many forms of neurodegeneration, stroke and acute neurotrauma. Tuxworth et al. show that inhibiting the DNA damage sensing response is neuroprotective, axon regenerative and improves functional recovery in models of neurodegeneration and optic nerve and spinal cord injury.
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 Aβ
1-42
-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.
Graphical Abstract