tRNA-Derived Fragments in Alzheimer’s Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms

Article type: Research Article

Authors: Wu, Wenzhe^a | Lee, Inhan^b | Spratt, Heidi^{c; d} | Fang, Xiang^e | Bao, Xiaoyong^{a; d; f; g; *}

Affiliations: [a] Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX, USA | [b] miRcore, Ann Arbor, MI, USA | [c] Department of Preventive Medicine and Population Health, The University of Texas Medical Branch, Galveston, TX, USA | [d] The Institute of Translational Sciences, The University of Texas Medical Branch, Galveston, TX, USA | [e] Department of Neurology and Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA | [f] Sealy Center for Molecular Medicine, and The University of Texas Medical Branch, Galveston, TX, USA | [g] The Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX, USA

Correspondence: [*] Correspondence to: Xiaoyong Bao, PhD, Division of Clinical and Experimental Immunology & Infectious Diseases, Department of Pediatrics, 301 University Boulevard, Galveston, TX 77555 0372, USA. Tel.: +1 409 772 1777; Fax: +1 409 772 0460; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known. Objective:This study aimed to explore whether tRFs are involved in human AD. Methods:Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes. Results:tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage. Conclusion:Our studies demonstrated for the first time the involvement of tRFs in human AD.

Keywords: Alzheimer’s disease, biomarkers, neuropathology, small non-coding RNAs, tRNA-derived RNA fragments

DOI: 10.3233/JAD-200917

Journal: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 793-806, 2021