5'ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis
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'. 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 is cleaved by angiogenin and identified 5'ValCAC transfer-derived stress-induced RNA 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 transfer RNA fragment.
Health Research Board (HRB_POR/2013/348)
Thierry Latran Foundation (FTL AP2011 PREHN)
Science Foundation Ireland (17/JPND/3455 and SFI FutureNeuro Research Centre 16/RC/3948 co-funded under the European Regional Development Fund and by FutureNeuro industry partners)
Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme)
Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALSCarE project), funded through the EU Joint Programme– Neurodegenerative Disease Research.
Netherlands Organization for Health Research and Development (Veni scheme)
The Thierry Latran foundation and the Netherlands ALS foundation (Stichting ALS Nederland)
‘Fondazione Regionale per la Ricerca Biomedica’ (TRANSALS project)
ALS Association (20-IIP-513)
CommentsThe original article is available at https://academic.oup.com/
Published CitationHogg MC. et al. 5'ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis. Brain Commun. 2020 Aug 28;2(2):fcaa138.
Publication Date28 August 2020
- Physiology and Medical Physics
- Undergraduate Research
PublisherOxford University Press
- Published Version (Version of Record)