Journal
BRAIN COMMUNICATIONS
Volume 2, Issue 2, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/braincomms/fcaa138
Keywords
amyotrophic lateral sclerosis; angiogenin; tRNA fragment; tiRNA; biomarker
Categories
Funding
- Health Research Board [HRB_POR/2013/348]
- Thierry Latran Foundation (FTL AP2011 PREHN)
- Science Foundation Ireland [17/JPND/3455]
- Science Foundation Ireland (SFI FutureNeuro Research Centre) [16/RC/3948]
- European Regional Development Fund
- FutureNeuro
- Netherlands ALS Foundation
- Netherlands Organization for Health Research and Development (Vici scheme)
- Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project) through EU Joint Programme-Neurodegenerative Disease Research, (JPND)
- Netherlands Organization for Health Research and Development (Veni scheme)
- Thierry Latran foundation
- Netherlands ALS foundation (Stichting ALS Nederland)
- 'Fondazione Regionale per la Ricerca Biomedica' (TRANS-ALS project)
- ALS Association [20-IIP-513]
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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'. 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 SOD1(G93A) 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 SOD1(G93A) mice may result from elevated levels of 5'ValCAC transfer RNA fragment.
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