Investigation of Self-Nucleic Acids as a Trigger for Neuroinflammation

PROJECT SUMMARY Pattern recognition receptors (PRRs) are an essential component of the innate immune system responsible for detecting invading pathogens and activating appropriate immunological responses. A significant proportion of PRRs are specialized in detecting viral DNA or RNA. Since DNA and RNA are the basic building blocks of life

across all species, an intriguing and widely unexplored question emerges: Can PRRs detect endogenous (self) DNA or RNA, and what is the biological significance of self-nucleic acid detection? My laboratory at Columbia University seeks to understand the biological significance of self-RNA sensing by PRRs during both homeostasis

and disease, and to further elucidate how self-RNA sensing is regulated to prevent autoimmune disorders. Research on Aicardi-Goutières syndrome (AGS) uncovered the causal role of self-nucleic acid mediated PRR activation in autoimmunity. AGS symptoms `mimic' viral infection, as patients exhibit elevated levels of type I

interferon (IFN), a potent antiviral cytokine produced when PRRs detect viral nucleic acids. Mutations in the RNA editing enzyme ADAR1 can cause AGS. ADAR1 introduces A-to-I edits in cellular double-stranded RNAs (dsRNAs), and prior studies demonstrated that ADAR1 deficiency leads to aberrant activation of PKR and MDA5,

two PRRs widely known to sense viral dsRNAs and trigger potent antiviral immune responses. These findings gave rise to the idea that during ADAR1 deficiency, self-RNAs become mistaken as viral RNAs, triggering PRR activation and downstream antiviral and inflammatory responses. Intriguingly, AGS mainly affects the brain,

where elevated type I IFN production is observed, and most patients are left with mental and physical disabilities due to damage to the brain. ADAR1 and many PRRs are ubiquitously expressed in all cells, but it is puzzling why the neural compartment is particularly vulnerable to dysregulated inflammation. Currently the underlying

molecular mechanisms that predispose the brain to inflammation are poorly defined. Our long-term goal is to define the role of self-RNAs in triggering neuroinflammation. We will determine if dsRNA sensing PRRs contribute to constitutive type I IFN expression in human neural cells, including neurons (Aim 1). Then, we will

determine the abundance and subcellular localization of dsRNAs in neurons: during homeostasis and RNA dysregulation (Aim 2). We will also elucidate the molecular mechanism by which ADAR1 restricts self-RNAs from activating PRRs in neural cells (Aim 3). In this application our rich experience in immunology and RNA biology

will be applied to neurobiology. We will utilize cutting edge human stem cell technology, neural cell differentiation techniques, and high-throughput genomics in collaboration with leading experts in their field. These studies can help identify early molecular events that trigger inflammation in the brain, which may lead to discovery of new

therapeutic targets to treat AGS. More broadly, these studies may provide insight into how inflammation arises in other neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis) or frontotemporal dementia (FTD), where perturbation of RNA-binding protein dosage or expanded RNA repeat elements can cause disease.