Differential DNA damage vulnerability in human neuropathies

The maintenance of genomic integrity is a fundamental prerequisite for tissue homeostasis, which is critical for central nervous system (CNS) function. During neurogenesis, the transition from rapidly proliferating neuroprogenitors to post-mitotic neurons entails a fundamental shift in genotoxic threats, which must be addressed by the robust DNA damage response (DDR) network. The spatiotemporal utilisation of distinct DDR pathways in different neural cell types establishes heterogeneous vulnerabilities in specific brain regions to pathological processes. While the cerebrum exhibits varying or negligible degrees of sensitivity to DDR defects, cerebellar atrophy and degeneration are common hallmarks of various human genomic instability syndromes (GIS). Biomedical and cellular studies of human GIS and the corresponding mouse models have shed light on the aetiology of the associated neuropathies; however, cerebellar vulnerability to DDR defects remains poorly understood. Here, we review the cell type- and species-specific divergences in DDR reliance in different brain regions, along with the corresponding DDR pathways underpinning the distinct susceptibility of neuropathological manifestations.