Elucidating the role of immunostimulatory dsRNAs in neurodegeneration

Modern biology is entering the RNA-age. New discoveries have expanded the role of RNA beyond just a messenger for protein synthesis. The highly dynamic nature of RNA structure is key to diversifying RNA function. Notably, certain RNA structures can act as molecules that stimulate immune responses. Our group recently discovered that human neurons are highly enriched for long double-stranded RNA (dsRNA) structures, which form when two complementary RNA strands bind together. This was surprising because long dsRNAs are commonly formed by viral RNAs and are potent stimulators of immunity, but neurons formed these structures from self-RNA in the absence of infection. We found that these neuronal dsRNAs are derived from the long 3’ untranslated regions (UTRs) of mRNAs and, like viral dsRNAs, neuronal dsRNAs also stimulate immune responses. Why are neurons expressing immunostimulatory RNAs that resemble viral RNAs? What do these dsRNAs do in healthy and diseased neurons? The MIND Prize will allow us to examine these fascinating questions. Ultimately, we hope our investigations can lead to novel RNA-targeting or inflammation-targeting therapeutics to treat neurodegenerative diseases.

Dr. Hachung Chung is an Assistant Professor in the Department of Microbiology and Immunology at Columbia University Vagelos College of Physicians and Surgeons. She earned her Ph.D. degree in Microbiology and Molecular Genetics from Harvard University in the laboratory of Dr. Dennis Kasper. Her thesis demonstrated that the mammalian gut requires ‘host-specific’ bacterial species for proper immune maturation. She conducted her post-doctoral training at The Rockefeller University with Dr. Charles Rice, where she demonstrated that our own RNAs can trigger pathologic autoinflammation. At Columbia University, Dr. Chung’s research team aims to gain a better understanding of how our immune system suppresses harmful immune responses to self-ligands (specifically self-RNAs), while mounting a rapid immune response to pathogens. These studies can serve as a basis for further translational research and future therapeutics since self-ligand sensing by our immune system can cause numerous autoimmune disorders and neurodegenerative diseases. Hachung is also a recipient of the Searle Scholars award (2020).

A central concept in immunology is the idea that our immune system can selectively respond to foreign (‘non-self’) ligands, while evading immune responses against ‘self’-ligands. Pattern recognition receptors (PRRs) are an essential component of this self vs. non-self recognition system as they are responsible for detecting non-self 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 question emerges: Can PRRs detect our own DNA or RNA, and what is the biological significance? Our laboratory recently discovered that neurons are a unique cell type that carries exceptionally high levels of double-stranded RNA (dsRNA) structures that constantly activate PRRs even in homeostasis. We found that these immunostimulatory dsRNA structures are critical for antiviral defense but could also cause toxic inflammation when RNA homeostasis is disrupted in neurons.

"We discovered that neurons express RNA structures that resemble viral RNAs and these neuronal RNAs constantly stimulate an immune response. It appears as if neurons are faking an infection! Why would neurons do this, and what would happen when disease strikes? The MIND Prize now allows us to study what immunostimulatory RNAs do in healthy and diseased brains."

Our MIND application will explore a new paradigm that autoinflammatory reactions against our own RNAs is an early event that initiates and accelerates age-related neurodegeneration, paving the way for a multidisciplinary research program at the intersection of immunology, neuroscience, and RNA biology. These studies can potentially open opportunities to develop inflammation-targeting or RNA-targeting therapeutics to treat neural disorders.