tRNA-Derived RNA Fragments and Their Potential Role in Mediating Multiple Sclerosis Associated with Epstein-Barr Virus

Our research proposal responds to Funding Opportunity Number HT942524MSRPEHDA, under the Multiple Sclerosis (MS) Research Program's Exploration-Hypothesis Development Award category. This proposal seeks to investigate the role of the Epstein-Barr virus (EBV) in the etiology of MS, focusing on the potential contribution of EBV-affected non-coding RNAs (ncRNAs) to MS pathogenesis. In particular, we will explore the recently identified family of small ncRNAs (sncRNAs) known as tRNA-derived RNA fragments (tRFs). The findings from this study could offer new insights into MS disease mechanisms and pave the way for developing preventive and therapeutic strategies to combat the disease. The importance of tRFs in neurodegenerative diseases. My research has focused on host-virus interactions, particularly those involving respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2. We discovered that tRFs, a family of sncRNAs enriched with epigenetic modifications, are the most significantly affected sncRNAs by RSV infection. This breakthrough was made possible by our optimization of barcode ligation for modification-enriched ncRNAs, enabling more accurate sncRNA sequencing. These differentiated tRFs are functional and virus-specific 1-9 , with growing evidence supporting their roles in other viral infections and diseases1,10-13 . In collaboration with Dr. Xiang Fang, co-I and Clinic Medical Director of our Neurology Service, as well as Director of the Collaborative Alzheimer's Disease and Memory Disorders (CADMD) program at UTMB, we identified tRFs as the most significantly affected sncRNAs in the hippocampus of AD patients. Notably, changes were predominantly observed in five tRFs, with one, tRF5-ProAGG, showing a correlation with AD severity but not with aging14 . This correlation was also detected in serum samples, further supporting the potential of tRFs as promising biomarkers for AD diagnosis and prognosis. Additionally, we found that transfection of an AD-relevant tRF altered the expression of genes involved in AD progression 15 . Concurrently, other studies have demonstrated the involvement of tRFs in additional neurodegenerative diseases, including Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) 16-19 , further reinforcing the broader significance of tRFs in neurodegenerative conditions.