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

DNA double-strand breaks (DSBs) 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 (DDR) in response to DSBs 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 DDR might be neuroprotective. Here, we show that attenuating the DDR by targeting the MRN complex, which is responsible for recognition of DSBs, is neuroprotective in three neurodegeneration models in Drosophila and prevents amyloid-beta-induced loss of synapses in hippocampal neurons. Attenuating the DDR after optic nerve injury is also neuroprotective to retinal ganglion cells (RGC) and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DDR is targeted in vitro and this strategy also induces a full restoration of lost function after spinal cord injury in vivo. We conclude that muting the DDR in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.