Genome Maintenance and Nervous System Function

Genome stability is critically important for human health, particularly that of the nervous system. This is apparent from inherited DNA repair deficiency syndromes that manifest neurodegeneration, neurodevelopmental disorders or brain tumors. Defects in genome maintenance are also implicated in broader neurologic health issues, including age-related degenerative events that mar cognitive ability and impact quality of life. Therefore, understanding the mechanistic connections between faulty DNA damage signaling and human disease is of fundamental biomedical importance. However, the underlying basis for pathology associated with DNA repair deficiency remains mostly unknown. We have developed new murine models of neurodegeneration in the context of defective DNA repair pathways that underpin human disease. These new disease models manifest progressive ataxia and profound defects in cerebellar function, which are key hallmarks of many human DNA repair deficiency syndromes. The neurodegeneration phenotype in the DNA repair deficiency models arises from transcriptional disruption that substantially perturbs key regulators of cerebellar homeostasis. These transcriptional defects result from RNA splicing abnormalities and aberrant R-Loop formation (a potentially genotoxic three-stranded nucleic acid structure involving a DNA:RNA hybrid). Importantly, chronic genome instability throughout the cerebellum selectively impacts Purkinje cells (PC), as intron retention and R-Loop accumulation predominantly involves PC-expressed genes. These data provide an explanation for how genome instability causes neurodegeneration and promotes ataxia.