King's College London

Research portal

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

Research output: Contribution to journalArticlepeer-review

Roberto Simone, Faiza Javad, Warren Emmett, Oscar G. Wilkins, Filipa Lourenço Almeida, Natalia Barahona-Torres, Justyna Zareba-Paslawska, Mazdak Ehteramyan, Paola Zuccotti, Angelika Modelska, Kavitha Siva, Gurvir S. Virdi, Jamie S. Mitchell, Jasmine Harley, Victoria A. Kay, Geshanthi Hondhamuni, Daniah Trabzuni, Mina Ryten, Selina Wray, Elisavet Preza & 14 more Demis A. Kia, Alan Pittman, Raffaele Ferrari, Claudia Manzoni, Andrew Lees, John A. Hardy, Michela A. Denti, Alessandro Quattrone, Rickie Patani, Per Svenningsson, Thomas T. Warner, Vincent Plagnol, Jernej Ule, Rohan de Silva

Original languageEnglish
Pages (from-to)117-123
Number of pages7
JournalNature
Volume594
Issue number7861
DOIs
Published3 Jun 2021

Bibliographical note

Funding Information: Research UK (R.d.S.), Alzheimer’s Research UK to R.d.S.; a BBSRC LiDo PhD studentship to F.J.; an AgeUK PhD Studentship to V.A.K.; the NIHR Queen Square Dementia BRU to S.W., E.P. and J.A.H.; the Italian Ministry of Education, University and Research Futuro in Ricerca (RBFR-0895DC) ‘Mechanisms of post-transcriptional regulation of gene expression in dementias’ to M.A.D.; University of Trento PhD studentship and an IBRO InEurope Short Stay grant to K.S.; and the MRC Sudden Death Brain Bank. This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002) and the Wellcome Trust (FC001002). This research was funded in part by the Wellcome Trust (4 Year Wellcome Trust Studentship to O.G.W.) and by the European Research Council under the European Union’s Seventh Framework Programme (617837-Translate to J.U.) and under the European Union’s Horizon 2020 research and innovation programme (835300-RNPdynamics to J.U.). S.W. holds a Alzheimer’s Research UK Senior Research Fellowship (ARUK-SRFEXT2020-001); R.P. holds an MRC Senior Clinical Fellowship (MR/S006591/1). This work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK; Medical Research Council (award number MR/N026004/1 to J.A.H.), Wellcome Trust (award number 202903/Z/16/Z to J.A.H.), Dolby Family Fund to J.A.H., National Institute for Health Research University College London Hospitals Biomedical Research Centre funding to J.A.H. Funding Information: Acknowledgements We thank L. Wilson and A. Willis for providing pRF and pRhcvF luciferase reporter vectors; P. Fratta and A. Isaacs for suggestions and comments on the manuscript, and other members of the UK Brain Expression Consortium: S. Guelfi, K. D’Sa, M. Matarin, J. Vandrovcova, A. Ramasamy, J. A. Botia, C. Smith and P. Forabosco. This work was supported by the Reta Lila Weston Trust for Medical Research for funding to T.T.W., R.d.S. and R.S.; CBD Solutions for funding to R.d.S., R.S. and P.S.); the Medical Research Council (G0501560 to R.d.S.), Parkinson’s UK (K1212 to R.d.S.), PSP Association (R.d.S.), CurePSP (R.d.S.), Brain Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

King's Authors

Abstract

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson’s disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces—whereas silencing MAPT-AS1 expression increases—neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454