tRNA Fragment biomarkers of Neurological Disease: Challenges and Opportunities

Main Article Content

Marion C. Hogg

Abstract

Transfer RNAs play a crucial role in protein translation where they bring amino acids to the ribosome to be incorporated into nascent polypeptide chains. During stress conditions tRNAs can be cleaved to generate tRNA-derived fragments. Several ribonucleases have been identified that cleave tRNA, however mutations in the stress-induced ribonuclease Angiogenin have been identified in a range of neurological disorders including Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Alzheimer’s Disease, suggesting that tRNA cleavage may be dysregulated in neurological disease. tRNA fragments have been detected in biofluids indicating they may be of use as biomarkers for neurological diseases. There is considerable variability in the methods used to quantify tRFs from size selection, adapter ligation, removal of RNA modifications, and sequence analysis approaches which can make it difficult to reconcile multiple studies. Here we review the biology of transfer RNAs and the biogenesis of tRNA-derived fragments, with a focus on the methods used to identify and quantify tRNA fragments and how different methodological approaches can influence tRNA fragment detection. We provide an overview of current literature on the identification of tRNA fragments in neurological disease models and patient samples, with a focus on circulating tRNA fragments as potential biomarkers of neurological diseases.

Article Details

How to Cite
HOGG, Marion C.. tRNA Fragment biomarkers of Neurological Disease: Challenges and Opportunities. Medical Research Archives, [S.l.], v. 11, n. 3, mar. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3688>. Date accessed: 20 apr. 2024. doi: https://doi.org/10.18103/mra.v11i3.3688.
Section
Research Articles

References

1. Kim SH, Quigley GJ, Suddath FL, et al. Three-Dimensional Structure of Yeast Phenylalanine Transfer RNA: Folding of the Polynucleotide Chain. Science. 1973;179(4070):285-288. doi:10.1126/science.179.4070.285
2. Holley RW, Apgar J, Everett GA, et al. Structure of a Ribonucleic Acid. Science. 1965;147(3664):1462-1465. doi:10.1126/science.147.3664.1462
3. Kim SH, Suddath FL, Quigley GJ, et al. Three-Dimensional Tertiary Structure of Yeast Phenylalanine Transfer RNA. Science. 1974;185(4149):435-440. doi:10.1126/science.185.4149.435
4. Lindahl T, Adams A, Fresco JR. Renaturation of transfer ribonucleic acids through site binding of magnesium. Proc Natl Acad Sci USA. 1966;55(4):941-948. doi:10.1073/pnas.55.4.941
5. Thompson M, Haeusler RA, Good PD, Engelke DR. Nucleolar Clustering of Dispersed tRNA Genes. Science. 2003;302(5649):1399-1401. doi:10.1126/science.1089814
6. Chan PP, Lowe TM. GtRNAdb 2.0: an expanded database of transfer RNA genes identified in complete and draft genomes. Nucleic Acids Res. 2016;44(D1):D184-D189. doi:10.1093/nar/gkv1309
7. Ishimura R, Nagy G, Dotu I, et al. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science. 2014;345(6195):455-459. doi:10.1126/science.1249749
8. Klemm B, Wu N, Chen Y, et al. The Diversity of Ribonuclease P: Protein and RNA Catalysts with Analogous Biological Functions. Biomolecules. 2016;6(2):27. doi:10.3390/biom6020027
9. Hartmann RK, Gößringer M, Späth B, Fischer S, Marchfelder A. Chapter 8 The Making of tRNAs and More – RNase P and tRNase Z. In: Progress in Molecular Biology and Translational Science. Vol 85. Elsevier; 2009:319-368. doi:10.1016/S0079-6603(08)00808-8
10. Bertrand E, Houser-Scott F, Kendall A, Singer RH, Engelke DR. Nucleolar localization of early tRNA processing. Genes Dev. 1998;12(16):2463-2468. doi:10.1101/gad.12.16.2463
11. Wellner K, Betat H, Mörl M. A tRNA’s fate is decided at its 3′ end: Collaborative actions of CCA-adding enzyme and RNases involved in tRNA processing and degradation. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 2018;1861(4):433-441. doi:10.1016/j.bbagrm.2018.01.012
12. Hayne CK, Lewis TA, Stanley RE. Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex. WIREs RNA. 2022;13(5). doi:10.1002/wrna.1717
13. Popow J, Englert M, Weitzer S, et al. HSPC117 Is the Essential Subunit of a Human tRNA Splicing Ligase Complex. Science. 2011;331(6018):760-764. doi:10.1126/science.1197847
14. Schaffer AE, Eggens VRC, Caglayan AO, et al. CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration. Cell. 2014;157(3):651-663. doi:10.1016/j.cell.2014.03.049
15. Budde BS, Namavar Y, Barth PG, et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008;40(9):1113-1118. doi:10.1038/ng.204
16. Appelhof B, Barth PG, Baas F. Classification of Pontocerebellar Hypoplasia: Where does it End? EMJ Neurol. Published online August 13, 2019:52-61. doi:10.33590/emjneurol/10311303
17. Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR. Identification of a Human Endonuclease Complex Reveals a Link between tRNA Splicing and Pre-mRNA 3′ End Formation. Cell. 2004;117(3):311-321. doi:10.1016/S0092-8674(04)00342-3
18. Hanada T, Weitzer S, Mair B, et al. CLP1 links tRNA metabolism to progressive motor-neuron loss. Nature. 2013;495(7442):474-480. doi:10.1038/nature11923
19. Pan T. Modifications and functional genomics of human transfer RNA. Cell Res. 2018;28(4):395-404. doi:10.1038/s41422-018-0013-y
20. Schaefer M, Pollex T, Hanna K, et al. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 2010;24(15):1590-1595. doi:10.1101/gad.586710
21. Tuorto F, Liebers R, Musch T, et al. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol. 2012;19(9):900-905. doi:10.1038/nsmb.2357
22. Blanco S, Dietmann S, Flores JV, et al. Aberrant methylation of t RNA s links cellular stress to neuro‐developmental disorders. EMBO J. 2014;33(18):2020-2039. doi:10.15252/embj.201489282
23. Alexandrov A, Chernyakov I, Gu W, et al. Rapid tRNA Decay Can Result from Lack of Nonessential Modifications. Molecular Cell. 2006;21(1):87-96. doi:10.1016/j.molcel.2005.10.036
24. Suzuki T. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol. 2021;22(6):375-392. doi:10.1038/s41580-021-00342-0
25. Boccaletto P, Stefaniak F, Ray A, et al. MODOMICS: a database of RNA modification pathways. 2021 update. Nucleic Acids Research. 2022;50(D1):D231-D235. doi:10.1093/nar/gkab1083
26. Spaulding EL, Hines TJ, Bais P, et al. The integrated stress response contributes to tRNA synthetase–associated peripheral neuropathy. Science. 2021;373(6559):1156-1161. doi:10.1126/science.abb3414
27. Zuko A, Mallik M, Thompson R, et al. tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase. Science. 2021;373(6559):1161-1166. doi:10.1126/science.abb3356
28. Waldron C, Lacroute F. Effect of growth rate on the amounts of ribosomal and transfer ribonucleic acids in yeast. J Bacteriol. 1975;122(3):855-865. doi:10.1128/jb.122.3.855-865.1975
29. Palazzo AF, Lee ES. Non-coding RNA: what is functional and what is junk? Front Genet. 2015;6. doi:10.3389/fgene.2015.00002
30. Torrent M, Chalancon G, de Groot NS, Wuster A, Madan Babu M. Cells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions. Sci Signal. 2018;11(546):eaat6409. doi:10.1126/scisignal.aat6409
31. Pang YLJ, Abo R, Levine SS, Dedon PC. Diverse cell stresses induce unique patterns of tRNA up- and down-regulation: tRNA-seq for quantifying changes in tRNA copy number. Nucleic Acids Research. 2014;42(22):e170-e170. doi:10.1093/nar/gku945
32. Greenway MJ, Andersen PM, Russ C, et al. ANG mutations segregate with familial and “sporadic” amyotrophic lateral sclerosis. Nat Genet. 2006;38(4):411-413. doi:10.1038/ng1742
33. Sebastià J, Kieran D, Breen B, et al. Angiogenin protects motoneurons against hypoxic injury. Cell Death Differ. 2009;16(9):1238-1247. doi:10.1038/cdd.2009.52
34. Dyer KD. The mouse RNase 4 and RNase 5/ang 1 locus utilizes dual promoters for tissue-specific expression. Nucleic Acids Research. 2005;33(3):1077-1086. doi:10.1093/nar/gki250
35. Shapiro R, Riordan JF, Vallee BL. Characteristic ribonucleolytic activity of human angiogenin. Biochemistry. 1986;25(12):3527-3532. doi:10.1021/bi00360a008
36. Fu H, Feng J, Liu Q, et al. Stress induces tRNA cleavage by angiogenin in mammalian cells. FEBS Letters. 2009;583(2):437-442. doi:10.1016/j.febslet.2008.12.043
37. Yamasaki S, Ivanov P, Hu G fu, Anderson P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. Journal of Cell Biology. 2009;185(1):35-42. doi:10.1083/jcb.200811106
38. Sorrentino S. The eight human “canonical” ribonucleases: Molecular diversity, catalytic properties, and special biological actions of the enzyme proteins. FEBS Letters. 2010;584(11):2194-2200. doi:10.1016/j.febslet.2010.04.018
39. Li G, Manning AC, Bagi A, et al. Distinct Stress‐Dependent Signatures of Cellular and Extracellular tRNA‐Derived Small RNAs. Advanced Science. 2022;9(17):2200829. doi:10.1002/advs.202200829
40. Nechooshtan G, Yunusov D, Chang K, Gingeras TR. Processing by RNase 1 forms tRNA halves and distinct Y RNA fragments in the extracellular environment. Nucleic Acids Research. 2020;48(14):8035-8049. doi:10.1093/nar/gkaa526
41. Haussecker D, Huang Y, Lau A, Parameswaran P, Fire AZ, Kay MA. Human tRNA-derived small RNAs in the global regulation of RNA silencing. RNA. 2010;16(4):673-695. doi:10.1261/rna.2000810
42. Di Fazio A, Schlackow M, Pong SK, Alagia A, Gullerova M. Dicer dependent tRNA derived small RNAs promote nascent RNA silencing. Nucleic Acids Research. 2022;50(3):1734-1752. doi:10.1093/nar/gkac022
43. Provost P. Ribonuclease activity and RNA binding of recombinant human Dicer. The EMBO Journal. 2002;21(21):5864-5874. doi:10.1093/emboj/cdf578
44. Dhahbi JM, Spindler SR, Atamna H, et al. 5′ tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genomics. 2013;14(1):298. doi:10.1186/1471-2164-14-298
45. Godoy PM, Bhakta NR, Barczak AJ, et al. Large Differences in Small RNA Composition Between Human Biofluids. Cell Reports. 2018;25(5):1346-1358. doi:10.1016/j.celrep.2018.10.014
46. Srinivasan S, Yeri A, Cheah PS, et al. Small RNA Sequencing across Diverse Biofluids Identifies Optimal Methods for exRNA Isolation. Cell. 2019;177(2):446-462.e16. doi:10.1016/j.cell.2019.03.024
47. Zheleznyakova GY, Piket E, Needhamsen M, et al. Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology. Proc Natl Acad Sci U S A. 2021;118(17):e2011574118. doi:10.1073/pnas.2011574118
48. Hogg MC, Rayner M, Susdalzew S, et al. 5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis. Brain Communications. 2020;2(2):fcaa138. doi:10.1093/braincomms/fcaa138
49. Appierto V, Callari M, Cavadini E, Morelli D, Daidone MG, Tiberio P. A lipemia-independent NanoDrop ® -based score to identify hemolysis in plasma and serum samples. Bioanalysis. 2014;6(9):1215-1226. doi:10.4155/bio.13.344
50. Cozen AE, Quartley E, Holmes AD, Hrabeta-Robinson E, Phizicky EM, Lowe TM. ARM-seq: AlkB-facilitated RNA methylation sequencing reveals a complex landscape of modified tRNA fragments. Nat Methods. 2015;12(9):879-884. doi:10.1038/nmeth.3508
51. Zheng G, Qin Y, Clark WC, et al. Efficient and quantitative high-throughput tRNA sequencing. Nat Methods. 2015;12(9):835-837. doi:10.1038/nmeth.3478
52. Pichot F, Hogg MC, Marchand V, et al. Quantification of substoichiometric modification reveals global tsRNA hypomodification, preferences for angiogenin-mediated tRNA cleavage, and idiosyncratic epitranscriptomes of human neuronal cell-lines. Computational and Structural Biotechnology Journal. 2023;21:401-417. doi:10.1016/j.csbj.2022.12.020
53. Wang X, Matuszek Z, Huang Y, et al. Queuosine modification protects cognate tRNAs against ribonuclease cleavage. RNA. 2018;24(10):1305-1313. doi:10.1261/rna.067033.118
54. Yeri A, Courtright A, Danielson K, et al. Evaluation of commercially available small RNASeq library preparation kits using low input RNA. BMC Genomics. 2018;19(1):331. doi:10.1186/s12864-018-4726-6
55. Avcilar-Kucukgoze I, Gamper H, Polte C, et al. tRNAArg-Derived Fragments Can Serve as Arginine Donors for Protein Arginylation. Cell Chemical Biology. 2020;27(7):839-849.e4. doi:10.1016/j.chembiol.2020.05.013
56. Liu Z, Kim HK, Xu J, Jing Y, Kay MA. The 3’tsRNAs are aminoacylated: Implications for their biogenesis. Chen Q, ed. PLoS Genet. 2021;17(7):e1009675. doi:10.1371/journal.pgen.1009675
57. Loher P, Telonis AG, Rigoutsos I. MINTmap: fast and exhaustive profiling of nuclear and mitochondrial tRNA fragments from short RNA-seq data. Sci Rep. 2017;7(1):41184. doi:10.1038/srep41184
58. Murillo-Recio M, Martínez de Lejarza Samper IM, Tuñí i Domínguez C, Ribas de Pouplana L, Torres AG. tRNAstudio: facilitating the study of human mature tRNAs from deep sequencing datasets. Kendziorski C, ed. Bioinformatics. 2022;38(10):2934-2936. doi:10.1093/bioinformatics/btac198
59. Selitsky SR, Sethupathy P. tDRmapper: challenges and solutions to mapping, naming, and quantifying tRNA-derived RNAs from human small RNA-sequencing data. BMC Bioinformatics. 2015;16(1):354. doi:10.1186/s12859-015-0800-0
60. Joilin G, Gray E, Thompson AG, et al. Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis. Brain Commun. 2020;2(1):fcaa053. doi:10.1093/braincomms/fcaa053
61. Gagliardi S, Davin A, Bini P, et al. A Novel Nonsense Angiogenin Mutation is Associated With Alzheimer Disease. Alzheimer Disease & Associated Disorders. 2019;33(2):163-165. doi:10.1097/WAD.0000000000000272
62. van Es MA, Schelhaas HJ, van Vught PWJ, et al. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. Ann Neurol. 2011;70(6):964-973. doi:10.1002/ana.22611
63. Rayaprolu S, Soto-Ortolaza A, Rademakers R, Uitti RJ, Wszolek ZK, Ross OA. Angiogenin variation and Parkinson disease. Ann Neurol. 2012;71(5):725-727. doi:10.1002/ana.23586
64. Su Z, Kuscu C, Malik A, Shibata E, Dutta A. Angiogenin generates specific stress-induced tRNA halves and is not involved in tRF-3–mediated gene silencing. Journal of Biological Chemistry. 2019;294(45):16930-16941. doi:10.1074/jbc.RA119.009272
65. Li X, Liu X, Zhao D, et al. tRNA-derived small RNAs: novel regulators of cancer hallmarks and targets of clinical application. Cell Death Discov. 2021;7(1):249. doi:10.1038/s41420-021-00647-1
66. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. The Lancet. 2021;397(10284):1577-1590. doi:10.1016/S0140-6736(20)32205-4
67. Sims R, Hill M, Williams J. The multiplex model of the genetics of Alzheimer’s disease. Nat Neurosci. 2020;23(3):311-322. doi:10.1038/s41593-020-0599-5
68. Zhang S, Li H, Zheng L, Li H, Feng C, Zhang W. Identification of functional tRNA-derived fragments in senescence-accelerated mouse prone 8 brain. Aging. 2019;11(22):10485-10498. doi:10.18632/aging.102471
69. Jankowsky JL, Fadale DJ, Anderson J, et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Human Molecular Genetics. 2004;13(2):159-170. doi:10.1093/hmg/ddh019
70. Lu H, Liu L, Han S, et al. Expression of tiRNA and tRF in APP/PS1 transgenic mice and the change of related proteins expression. Ann Transl Med. 2021;9(18):1457-1457. doi:10.21037/atm-21-4318
71. Wu W, Lee I, Spratt H, Fang X, Bao X. tRNA-Derived Fragments in Alzheimer’s Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms. JAD. 2021;79(2):793-806. doi:10.3233/JAD-200917
72. Bloem BR, Okun MS, Klein C. Parkinson’s disease. The Lancet. 2021;397(10291):2284-2303. doi:10.1016/S0140-6736(21)00218-X
73. Magee R, Londin E, Rigoutsos I. TRNA-derived fragments as sex-dependent circulating candidate biomarkers for Parkinson’s disease. Parkinsonism Relat Disord. 2019;65:203-209. doi:10.1016/j.parkreldis.2019.05.035
74. Kern F, Fehlmann T, Violich I, et al. Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson’s disease progression. Nat Aging. 2021;1(3):309-322. doi:10.1038/s43587-021-00042-6
75. Yue T, Zhan X, Zhang D, et al. SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity. Science. 2021;372(6543):eaba4220. doi:10.1126/science.aba4220
76. Paldor I, Madrer N, Vaknine Treidel S, Shulman D, Greenberg DS, Soreq H. Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex, and Parkinson’s disease-related changes. J Neurochem. Published online November 10, 2022. doi:10.1111/jnc.15723
77. Stamelou M, Respondek G, Giagkou N, Whitwell JL, Kovacs GG, Höglinger GU. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol. 2021;17(10):601-620. doi:10.1038/s41582-021-00541-5
78. Simoes FA, Joilin G, Peters O, et al. Potential of Non-Coding RNA as Biomarkers for Progressive Supranuclear Palsy. IJMS. 2022;23(23):14554. doi:10.3390/ijms232314554
79. Stoyas CA, La Spada AR. The CAG–polyglutamine repeat diseases: a clinical, molecular, genetic, and pathophysiologic nosology. In: Handbook of Clinical Neurology. Vol 147. Elsevier; 2018:143-170. doi:10.1016/B978-0-444-63233-3.00011-7
80. Bañez-Coronel M, Porta S, Kagerbauer B, et al. A Pathogenic Mechanism in Huntington’s Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity. Pearson CE, ed. PLoS Genet. 2012;8(2):e1002481. doi:10.1371/journal.pgen.1002481
81. Creus-Muncunill J, Guisado-Corcoll A, Venturi V, et al. Huntington’s disease brain-derived small RNAs recapitulate associated neuropathology in mice. Acta Neuropathol. 2021;141(4):565-584. doi:10.1007/s00401-021-02272-9
82. Kuriakose D, Xiao Z. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. IJMS. 2020;21(20):7609. doi:10.3390/ijms21207609
83. Huang L, Guo H, Cheng M, Zhao Y, Jin X. The Kinetic Change of the Serum Angiogenin Level in Patients with Acute Cerebral Infarction. Eur Neurol. 2007;58(4):224-227. doi:10.1159/000107944
84. Li Q, Hu B, Hu GW, et al. tRNA-Derived Small Non-Coding RNAs in Response to Ischemia Inhibit Angiogenesis. Sci Rep. 2016;6:20850. doi:10.1038/srep20850
85. Winek K, Soreq H, Meisel A. Regulators of cholinergic signaling in disorders of the central nervous system. J Neurochem. 2021;158(6):1425-1438. doi:10.1111/jnc.15332
86. Nguyen TTM, van der Bent ML, Wermer MJH, et al. Circulating tRNA Fragments as a Novel Biomarker Class to Distinguish Acute Stroke Subtypes. Int J Mol Sci. 2020;22(1):135. doi:10.3390/ijms22010135
87. Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. The Lancet Neurology. 2017;16(12):987-1048. doi:10.1016/S1474-4422(17)30371-X
88. Puhakka N, Das Gupta S, Vuokila N, Pitkänen A. Transfer RNA-Derived Fragments and isomiRs Are Novel Components of Chronic TBI-Induced Neuropathology. Biomedicines. 2022;10(1):136. doi:10.3390/biomedicines10010136
89. Di Pietro V, O’Halloran P, Watson CN, et al. Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM). Br J Sports Med. 2021;55(24):1395-1404. doi:10.1136/bjsports-2020-103274
90. Henshall DC, Hamer HM, Pasterkamp RJ, et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. The Lancet Neurology. 2016;15(13):1368-1376. doi:10.1016/S1474-4422(16)30246-0
91. Kuhlmann L, Lehnertz K, Richardson MP, Schelter B, Zaveri HP. Seizure prediction — ready for a new era. Nat Rev Neurol. 2018;14(10):618-630. doi:10.1038/s41582-018-0055-2
92. Hogg MC, Raoof R, El Naggar H, et al. Elevation of plasma tRNA fragments precedes seizures in human epilepsy. Journal of Clinical Investigation. 2019;129(7):2946-2951. doi:10.1172/JCI126346
93. Kiltschewskij DJ, Cairns MJ. Transcriptome-Wide Analysis of Interplay between mRNA Stability, Translation and Small RNAs in Response to Neuronal Membrane Depolarization. IJMS. 2020;21(19):7086. doi:10.3390/ijms21197086
94. Li H, Wu C, Aramayo R, Sachs MS, Harlow ML. Synaptic vesicles contain small ribonucleic acids (sRNAs) including transfer RNA fragments (trfRNA) and microRNAs (miRNA). Sci Rep. 2015;5(1):14918. doi:10.1038/srep14918
95. Wang Q, Lee I, Ren J, Ajay SS, Lee YS, Bao X. Identification and Functional Characterization of tRNA-derived RNA Fragments (tRFs) in Respiratory Syncytial Virus Infection. Molecular Therapy. 2013;21(2):368-379. doi:10.1038/mt.2012.237
96. Kapur M, Ganguly A, Nagy G, et al. Expression of the Neuronal tRNA n-Tr20 Regulates Synaptic Transmission and Seizure Susceptibility. Neuron. 2020;108(1):193-208.e9. doi:10.1016/j.neuron.2020.07.023
97. Qin C, Feng H, Zhang C, et al. Differential Expression Profiles and Functional Prediction of tRNA-Derived Small RNAs in Rats After Traumatic Spinal Cord Injury. Front Mol Neurosci. 2020;12:326. doi:10.3389/fnmol.2019.00326
98. Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3(1):17071. doi:10.1038/nrdp.2017.71
99. Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. doi:10.1038/s41572-018-0041-4
100. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
101. Needhamsen M, Khoonsari PE, Zheleznyakova GY, et al. Integration of small RNAs from plasma and cerebrospinal fluid for classification of multiple sclerosis. Front Genet. 2022;13:1042483. doi:10.3389/fgene.2022.1042483
102. McArdle H, Hogg MC, Bauer S, et al. Quantification of tRNA fragments by electrochemical direct detection in small volume biofluid samples. Sci Rep. 2020;10(1):7516. doi:10.1038/s41598-020-64485-4
103. Ishida T, Inoue T, Niizuma K, et al. Plasma tRNA derivatives concentrations for detecting early brain damage in patients with acute large vessel occlusion and predicting clinical outcomes after endovascular thrombectomy. Clinical Neurology and Neurosurgery. 2022;220:107358. doi:10.1016/j.clineuro.2022.107358