Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate aging in mice

Abstract

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc^−/− backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.

Keywords

TERC-53 / mitochondrial noncoding RNAs / brain aging / neuroinflammation / ubiquitination

References

[1] Barlow C, Hirotsune S, Paylor R et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 1996;86:159–171.

[2] Blasco MA, Rizen M, Greider CW et al. Differential regulation of telomerase activity and telomerase RNA during multi-stage tumorigenesis. Nat Genet 1996;12:200–204.

[3] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res 2002;30:e47.

[4] Cayuela ML, Flores JM, Blasco MA. The telomerase RNA component Terc is required for the tumour-promoting effects of Tert overexpression. EMBO Rep 2005;6:268–274.

[5] Chang S, Multani AS, Cabrera NG et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat Genet 2004;36:877–882.

[6] Cheng Y, Liu P, Zheng Q et al. Mitochondrial trafficking and processing of telomerase RNA TERC. Cell Rep 2018;24:2589–2595.

[7] Choudhury NR, Heikel G, Trubitsyna M et al. RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC Biol 2017;15:105.

[8] Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol 2016;37:608–620.

[9] Connell M, Chen H, Jiang J et al. HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development. Elife 2017;6:e28672.

[10] Cunningham C, Sanderson DJ. Malaise in the water maze: untangling the effects of LPS and IL-1beta on learning and memory. Brain Behav Immun 2008;22:1117–1127.

[11] Dionisio PA, Amaral JD, Rodrigues CMP. Oxidative stress and regulated cell death in Parkinson’s disease. Ageing Res Rev 2021;67:101263.

[12] Dobin A, Davis CA, Schlesinger F et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.

[13] Fatkin D, MacRae C, Sasaki T et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715–1724.

[14] Feng, J, WD Funk, SS Wang et al. The RNA component of human telomerase. Science 1995;269:1236–1241.

[15] Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018;15:505–522.

[16] Fleming A, Bourdenx M, Fujimaki M et al. The different autophagy degradation pathways and neurodegeneration. Neuron 2022;110:935–966.

[17] Gazzaniga FS, Blackburn EH. An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity. Blood 2014;124:3675–3684.

[18] Gebetsberger J, Polacek N. Slicing tRNAs to boost functional ncRNA diversity. RNA Biol 2013;10:1798–1806.

[19] Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 1989;337:331–337.

[20] Hall CL, Yang B, Yang X et al. Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 1995;82:19–26.

[21] Heldin P, Basu K, Olofsson B et al. Deregulation of hyaluronan synthesis, degradation and binding promotes breast cancer. J Biochem 2013;154:395–408.

[22] Ito H, Morishita R, Nagata KI. Autism spectrum disorder-associated genes and the development of dentate granule cells. Med Mol Morphol 2017;50:123–129.

[23] Jorda A, Aldasoro M, Aldasoro C et al. Inflammatory chemokines expression variations and their receptors in APP/PS1 mice. J Alzheimers Dis 2021;83:1051–1060.

[24] Ke BC, Huang XX, Li Y et al. Neuronal-derived Ccl7 drives neuropathic pain by promoting astrocyte proliferation. Neuroreport 2016;27:849–857.

[25] Keane M, Craig T, Alfoldi J et al. The naked mole rat genome resource: facilitating analyses of cancer and longevity-related adaptations. Bioinformatics 2014;30:3558–3560.

[26] Kim HK, Fuchs G, Wang S et al. A transfer-RNA-derived small RNA regulates ribosome biogenesis. Nature 2017;552:57–62.

[27] Lawrence M, Huber W, Pagès H et al. Software for computing and annotating genomic ranges. PLoS Comput Biol 2013;9:e1003118.

[28] Li H, Kroll T, Moll J et al. Spindle misorientation of cerebral and cerebellar progenitors is a mechanistic cause of megalencephaly. Stem Cell Rep 2017;9:1071–1080.

[29] Li D, Gao X, Ma X et al. Aging-induced tRNA(Glu)-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization. Cell Metab 2024;36:1059–1075.e9.

[30] Lipskaia L, Breau M, Cayrou C et al. mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema. EMBO Rep 2024;25:1650–1684.

[31] Liu H, Yang Y, Ge Y et al. TERC promotes cellular inflammatory response independent of telomerase. Nucleic Acids Res 2019;47:8084–8095.

[32] Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:550.

[33] Lu T, Pan Y, Kao SY et al. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429:883–891.

[34] Lu X, Huang J, Wu S et al. The tRNA-like small noncoding RNA mascRNA promotes global protein translation. EMBO Rep 2020;21:e49684.

[35] Mateo F, He Z, Mei L et al. Modification of BRCa1-associated breast cancer risk by HMMR overexpression. Nat Commun 2022;13:1895.

[36] Morin GB. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 1989;59:521–529.

[37] Nguyen THD, Tam J, Wu RA et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature 2018;557:190–195.

[38] Piechota M, Sunderland P, Wysocka A et al. Is senescence-associated beta-galactosidase a marker of neuronal senescence? Oncotarget 2016;7:81099–81109.

[39] Rahman AA, Soto-Avellaneda A, Yong Jin H et al. Enhanced hyaluronan signaling and autophagy dysfunction by VPS35 D620N. Neuroscience 2020;441:33–45.

[40] Reiman EM, Quiroz YT, Fleisher AS et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 e280A kindred: a case-control study. Lancet Neurol 2012;11:1048–1056.

[41] Sabouri M, Kordi M, Shabkhiz F et al. Moderate treadmill exercise improves spatial learning and memory deficits possibly via changing PDE-5, IL-1 beta and pCREB expression. Exp Gerontol 2020;139:111056.

[42] Sadiq MU, Langella S, Giovanello KS et al. Accrual of functional redundancy along the lifespan and its effects on cognition. Neuroimage 2021;229:117737.

[43] Shi M, Huang XY, Ren XY et al. AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1. Nat Cell Biol 2021;23:268–277.

[44] Sogorb-Esteve A, Swift IJ, Woollacott IOC et al. Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation. J Neuroinflammation 2021;18:224.

[45] Stern R. Go fly a Chitin: the mystery of Chitin and Chitinases in vertebrate tissues. Front Biosci (Landmark Ed) 2017;22:580–595.

[46] Tian X, Azpurua J, Hine C et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 2013;499:346–349.

[47] Ting NS, Pohorelic B, Yu Y et al. The human telomerase RNA component, hTR, activates the DNA-dependent protein kinase to phosphorylate heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res 2009;37:6105–6115.

[48] Varela I, Cadinanos J, Pendas AM et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 2005;437:564–568.

[49] Wang J, Li J, Wang Q et al. Dcf1 deficiency attenuates the role of activated microglia during neuroinflammation. Front Mol Neurosci 2018;11:256.

[50] Wang C, Gu Y, Zhou J et al. Leukocyte telomere length in children born following blastocyst-stage embryo transfer. Nat Med 2022;28:2646–2653.

[51] Wang Y, Wang M, Chen J et al. The gut microbiota reprograms intestinal lipid metabolism through long noncoding RNA Snhg9. Science 2023;381:851–857.

[52] Wilusz JE, Freier SM, Spector DL. 3’ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 2008;135:919–932.

[53] Xi L, Cech TR. Inventory of telomerase components in human cells reveals multiple subpopulations of hTR and hTERT. Nucleic Acids Res 2014;42:8565–8577.

[54] Yang B, Yang BL, Savani RC et al. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. EMBO J 1994;13:286–296.

[55] Yang C, Pang Y, Huang Y et al. Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow. Geroscience 2022;44:2139–2155.

[56] Yi X, Tesmer VM, Savre-Train I et al. Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Mol Cell Biol 1999;19:3989–3997.

[57] Zhang Z, Tian X, Lu JY et al. Increased hyaluronan by naked mole-rat HaS2 improves healthspan in mice. Nature 2023a;621:196–205.

[58] Zhang ZY, Harischandra DS, Wang R et al. TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease. Science 2023b;381:eadd6696.

[59] Zhao Q, Liu J, Deng H et al. Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output. Cell 2020;183:76–93.e22.

[60] Zheng Q, Liu P, Gao G et al. Mitochondrion-processed TERC regulates senescence without affecting telomerase activities. Protein Cell 2019;10:631–648.

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2024 The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.