Quantification of tRNA fragments by electrochemical direct detection in small volume biofluid samples

McArdle, Hazel; Hogg, Marion C.; Bauer, Sebastian; Rosenow, Felix; Prehn, Jochen H M; Adamson, Kellie; Henshall, David C.; Spain, Elaine

doi:10.1038/s41598-020-64485-4

Cited by 17 publications

(12 citation statements)

References 29 publications

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“…Serum tiRNAs are highly suited for development as biomarkers as they are stable, serum is easily accessible, and the custom Taqman assays described here are reliable and easy to perform. Further, we have recently developed an electrochemical direct detection method for quantification of tRNA fragments in small volume biofluids which could be utilized for prognostic profiling of patients upon entry into clinical trials ( McArdle et al , 2020 ). Therefore, we present a novel class of non-coding RNA, which may be of use as a prognostic biomarker indicating a protective neuronal stress response in ALS patients.…”

Section: Discussionmentioning

confidence: 99%

5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis

Hogg

Rayner

Susdalzew

et al. 2020

Brain Communications

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Loss-of-function mutations in the ribonuclease angiogenin are associated with amyotrophic lateral sclerosis. Angiogenin has been shown to cleave transfer RNAs during stress to produce ‘transfer-derived stress-induced RNAs’ (‘tiRNAs’). Stress-induced tRNA cleavage is preserved from single-celled organisms to humans indicating it represents part of a highly conserved stress response. However, to date the role of tRNA cleavage in amyotrophic lateral sclerosis remains to be fully elucidated. To this end, we performed small RNA sequencing on a human astrocytoma cell line to identify the complete repertoire of tRNA fragments generated by angiogenin. We found that only a specific subset of tRNAs are cleaved by angiogenin and identified 5’ValCAC tiRNA to be secreted from neural cells. 5’ValCAC was quantified in spinal cord and serum from SOD1G93A amyotrophic lateral sclerosis mouse models where we found it to be significantly elevated at symptom onset correlating with increased angiogenin expression, imbalanced protein translation initiation factors, and slower disease progression. In amyotrophic lateral sclerosis patient serum samples, we found 5’ValCAC to be significantly higher in patients with slow disease progression and interestingly we find 5’ValCAC to hold prognostic value for amyotrophic lateral sclerosis patients. Here we report that angiogenin cleaves a specific subset of tRNAs and provide evidence for 5’ValCAC as a prognostic biomarker in amyotrophic lateral sclerosis. We propose that increased serum 5’ValCAC levels indicate an enhanced angiogenin-mediated stress response within motor neurons that correlates with increased survival. These data suggest that the previously reported beneficial effects of angiogenin in SOD1G93A mice may result from elevated levels of 5’ValCAC tRNA fragment.

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Section: Discussionmentioning

confidence: 99%

5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis

Hogg

Rayner

Susdalzew

et al. 2020

Brain Communications

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“…Participant history confirms these observations were not confounded by medications or observed in individuals with psychogenic non-epileptogenic seizures, further supporting tRFs as a potential predictor of epilepsy [57]. A follow-up study identified a third tRF, 5'GlyGCC, using electrochemical detection methods and qPCR on patient whole blood [58]. Compared to other RNA species, investigations into the role tRFs play in the diagnosis and prognosis of epilepsy are less abundant.…”

Section: Trnas and Epilepsymentioning

confidence: 64%

Liquid Biopsies in Epilepsy: Biomarkers for Etiology, Diagnosis, Prognosis, and Therapeutics

Whitlock¹,

Soelter²,

Williams³

et al. 2021

Preprint

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Epilepsy is one of the most common disorders of the central nervous system, impacting nearly 50 million people around the world. Heterogeneous in nature, epilepsy presents in children and adults alike. Currently, surgery is the only treatment that can cure epilepsy. However, not all individuals are eligible or have successful outcomes. Difficulty in accessing samples of human brain tissue along with advances in sequencing technology have driven researchers to investigate sampling liquid biopsies in blood, serum, plasma, and cerebrospinal fluid within the context of epilepsy. Liquid biopsies provide minimal or non-invasive sample collection approaches and can be assayed relatively easily across multiple time points, unlike tissue-based sampling. Various efforts have investigated circulating nucleic acids from these samples including microRNAs, cell-free DNA, transfer RNAs, and long non-coding RNAs. Here, we review nucleic acid-based liquid biopsies in epilepsy to improve understanding of etiology, diagnosis, prediction, and therapeutic monitoring.

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“…For stroke biomarkers to be of clinical use, rapid detection is crucial. A recent paper demonstrated that rapid detection of low concentrations of tRFs in plasma is indeed feasible [ 12 ]. We found that tRFs were also detectable in plasma depleted of extracellular vesicles, suggesting that circulating tRFs are mainly present outside vesicles.…”

Section: Discussionmentioning

confidence: 99%

Circulating tRNA Fragments as a Novel Biomarker Class to Distinguish Acute Stroke Subtypes

Nguyễn

Bent

Wermer

et al. 2020

IJMS

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Early blood biomarkers to diagnose acute stroke could drastically reduce treatment delays. We investigated whether circulating small non-coding RNAs can serve as biomarkers to distinguish between acute ischemic stroke (IS), intracerebral hemorrhage (ICH) and stroke mimics (SM). In an ongoing observational cohort study, we performed small RNA-sequencing in plasma obtained from a discovery cohort of 26 patients (9 IS, 8 ICH and 9 SM) presented to the emergency department within 6 h of symptom onset. We validated our results in an independent dataset of 20 IS patients and 20 healthy controls. ICH plasma had the highest abundance of ribosomal and tRNA-derived fragments, while microRNAs were most abundant in plasma of IS patients. Combinations of four to five tRNAs yielded diagnostic accuracies (areas under the receiver operating characteristics curve) up to 0.986 (ICH vs. IS and SM) in the discovery cohort. Validation of the IS and SM models in the independent dataset yielded diagnostic accuracies of 0.870 and 0.885 to distinguish IS from healthy controls. Thus, we identified tRNA-derived fragments as a promising novel class of biomarkers to distinguish between acute IS, ICH and SM, as well as healthy controls.

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Quantification of tRNA fragments by electrochemical direct detection in small volume biofluid samples

Cited by 17 publications

References 29 publications

5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis

5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis

Liquid Biopsies in Epilepsy: Biomarkers for Etiology, Diagnosis, Prognosis, and Therapeutics

Circulating tRNA Fragments as a Novel Biomarker Class to Distinguish Acute Stroke Subtypes

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