MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

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, 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 and Rohan Silva ()
Additional contact information
Roberto Simone: UCL Queen Square Institute of Neurology
Faiza Javad: UCL Queen Square Institute of Neurology
Warren Emmett: UCL Genetics Institute
Oscar G. Wilkins: UCL Queen Square Institute of Neurology
Filipa Lourenço Almeida: UCL Queen Square Institute of Neurology
Natalia Barahona-Torres: UCL Queen Square Institute of Neurology
Justyna Zareba-Paslawska: Karolinska Institutet
Mazdak Ehteramyan: UCL Queen Square Institute of Neurology
Paola Zuccotti: Computational and Integrative Biology (CIBIO)
Angelika Modelska: Computational and Integrative Biology (CIBIO)
Kavitha Siva: Computational and Integrative Biology (CIBIO)
Gurvir S. Virdi: UCL Queen Square Institute of Neurology
Jamie S. Mitchell: UCL Queen Square Institute of Neurology
Jasmine Harley: UCL Queen Square Institute of Neurology
Victoria A. Kay: UCL Queen Square Institute of Neurology
Geshanthi Hondhamuni: UCL Queen Square Institute of Neurology
Daniah Trabzuni: UCL Queen Square Institute of Neurology
Mina Ryten: UCL Queen Square Institute of Neurology
Selina Wray: UCL Queen Square Institute of Neurology
Elisavet Preza: UCL Queen Square Institute of Neurology
Demis A. Kia: UCL Queen Square Institute of Neurology
Alan Pittman: St George’s University of London
Raffaele Ferrari: UCL Queen Square Institute of Neurology
Claudia Manzoni: Department of Pharmacology
Andrew Lees: UCL Queen Square Institute of Neurology
John A. Hardy: UCL Queen Square Institute of Neurology
Michela A. Denti: Computational and Integrative Biology (CIBIO)
Alessandro Quattrone: Computational and Integrative Biology (CIBIO)
Rickie Patani: UCL Queen Square Institute of Neurology
Per Svenningsson: Karolinska Institutet
Thomas T. Warner: UCL Queen Square Institute of Neurology
Vincent Plagnol: UCL Genetics Institute
Jernej Ule: UCL Queen Square Institute of Neurology
Rohan Silva: UCL Queen Square Institute of Neurology

Nature, 2021, vol. 594, issue 7861, 117-123

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03556-6

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