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As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration. Therefore, limiting the accumulation of DNA damage is essential for healthy neuronal populations. The naked mole rats (NMR) are from eastern Africa and can live for over three decades in chronically hypoxic environments. Despite their long lifespan, NMRs show little to no biological decline, neurodegeneration, or senescence. Here, we discuss molecular pathways and adaptations that NMRs employ to maintain genome integrity and combat the physiological and pathological decline in organismal function.

A hexanucleotide repeat expansion represents the most common genetic cause of\ud amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the\ud mechanisms by which the expansion cause neurodegeneration are poorly understood. We\ud report elevated levels of DNA/RNA hybrids (R-loops) and double-strand breaks (DSBs) in\ud rodent neurons, human cells, and in C9orf72-ALS patient spinal cord tissues.\ud Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated\ud DNA repair signalling and accumulation of protein-linked DNA breaks. We further\ud reveal that defective ATM-mediated DNA repair is a consequence of p62 accumulation,\ud which impairs H2A ubiquitylation and perturbs ATM signalling. Adeno-associated virus-\ud mediated expression of C9orf72-related RNA and dipeptide repeats in the murine central\ud nervous system causes elevated DSBs, ATM defects, and triggers neurodegeneration.\ud These findings identify R-Loops, DSBs, and defective ATM-mediated repair as\ud pathological consequences of C9orf72 expansions, and suggest that C9orf72-linked\ud neurodegeneration is driven, at least in part, by genomic instability.