Key roles for the innate immune response to genotoxic stress in neurological disease

Abstract

Abstract Mounting evidence indicates that DNA damage accumulation in the brain centrally contributes to a number of neurodevelopmental, psychiatric, and neurodegenerative disorders. Yet, little is currently known about the specific molecular pathways that the brain relies on to safeguard itself from DNA insults or how altered regulation of these pathways leads to neurological disease. In recent years, a number of new innate immune signaling pathways that respond to genotoxic stress have been identified. While many of these genomic sensors are highly expressed in the central nervous system (CNS), their roles in CNS homeostasis and disease remain poorly understood. In our recent unpublished studies, we have identified a novel DNA damage sensor that centrally contributes to both neurodevelopmental and neurodegenerative disease. Deletion of this genomic sensor in neurodevelopment was found to cause excessive DNA damage accumulation throughout the brain, abnormal CNS maturation, and the development of motor dysfunction, anxiety, and autism-related behaviors. Moreover, engagement of this DNA damage response in the adult brain was found to drive neurodegenerative disease. Interestingly, we observe that DNA damage-induced cytokine responses are not directly responsible for driving neurological disease in our model. In contrast, our findings using genetic knockout mouse strains, indicate that immune-based genomic sensors influence CNS function and health by regulating cell death signaling. Our studies demonstrate that DNA damage surveillance by the innate immune response coordinates the expulsion of genetically compromised cells from the brain and reveal novel roles for immune-based genomic sensors in CNS disease.