Effects of ALS-associated 5'tiRNA Gly-GCC on the transcriptomic and proteomic profile of primary neurons in vitro.

Autor: Jirström E; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland., Matveeva A; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland., Baindoor S; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland., Donovan P; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland., Ma Q; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Morrissey EP; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland., Arijs I; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, Leuven, Belgium., Boeckx B; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, Leuven, Belgium., Lambrechts D; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, Leuven, Belgium., Garcia-Munoz A; Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland., Dillon ET; Mass Spectrometry Resource, Conway Institute of Biomolecular & Biomedical Research, University College Dublin 4, Ireland., Wynne K; Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland., Ying Z; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Matallanas D; Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland., Hogg MC; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland., Prehn JHM; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; FutureNeuro Research Ireland Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland. Electronic address: prehn@rcsi.ie.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2024 Dec 22; Vol. 385, pp. 115128. Date of Electronic Publication: 2024 Dec 22.
DOI: 10.1016/j.expneurol.2024.115128
Abstrakt: tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5'tiRNA Gly-GCC , which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5'tiRNA Gly-GCC revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5'tiRNA Gly-GCC binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5'tiRNA Gly-GCC is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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