Regulated cGAS activation in HSV-1-associated neuropathogenesis.

Title: Regulated cGAS activation in HSV-1-associated neuropathogenesis Dementia is characterized by a progressive loss in memory and cognition. Alzheimer's disease (AD) is the most common dementia that has aging as the most significant risk factor. Genetics plays a major role in AD development and prognosis, which is further influenced by environmental factors, such as microbial infection. Herpes simplex viruses (HSV) are ubiquitous pathogens in the human population and reaches nearly 100% in citizens of 65 or older. HSV-1 is a neurotropic large DNA virus and implicated in AD development, representing a major environmental factor for AD and AD-related dementia. Inflammation is a common feature observed in brains of both AD model mice and human AD patients. One pathway triggering inflammation in the brain is the cytosolic DNA-mediated activation of cGAS and downstream inflammatory response. Though emerging studies implicate cytosolic DNA and cGAS in the development of AD and ADRD via provoking inflammation, a number of pressing questions remain unanswered. Central to these unanswered questions is the nature of cytosolic DNA and the regulation of DNA-cGAS-mediated innate immune activation. This proposal will address this question with a de novo synthesized DNA-protein crosslinker to profile the cytosolic cGAS-binding DNA in HSV-1-infected brain and probe the dynamic regulation of cGAS activation by a metabolic enzyme. This metabolic enzyme plays pivotal roles in regulating cGAS activation and downstream inflammatory response. Our work is expected to reveal molecular detail of cGAS activation and regulation by a metabolic enzyme in the neurodegeneration induced by a ubiquitous human pathogen.