Journal Article

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

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

2021

Overview

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes 1 , 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 site 3 . MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies 4 . Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies 5 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 IDPs 6 , with particular relevance for proteostasis in neurodegeneration. The natural antisense transcript MAPT-AS1 interferes with translation of mRNA transcript into tau protein in the brain and may represent a general mechanism for controlling levels of intrinsically disordered proteins, with particular relevance for neurodegeneration.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/44 / 14 / 14/1 / 14/19 / 14/63 / 38/101 / 38/32 / 38/39 / 38/88 / 38/89 / 38/91 / 42 / 45 / 631/337/384/2568 / 631/337/574 / 631/378/1689 / 631/378/340 / 631/553/2711 / 64/60 / Aged / Animals / Antisense RNA / Binding Sites / Brain / Brain - metabolism / Brain - pathology / Case-Control Studies / Cell Differentiation / Dementia disorders / Disease Progression / Epigenetics / Female / Frontotemporal dementia / Gene expression / Genomes / Haplotypes / Humanities and Social Sciences / Humans / Inclusions / Infections / Internal Ribosome Entry Sites - genetics / Male / Mice / Mice, Transgenic / Microtubules / Middle Aged / Movement disorders / multidisciplinary / Mutation / Neural coding / Neurodegeneration / Neurodegenerative diseases / Neurons - metabolism / Neurons - pathology / Parkinson's disease / Pathology / Protein Biosynthesis - genetics / Proteins / Proteostasis - genetics / Ribonucleic acid / Ribosomes - metabolism / Risk analysis / Risk factors / RNA / RNA, Antisense - genetics / rRNA / Science / Science (multidisciplinary) / Tau protein / tau Proteins - biosynthesis / tau Proteins - genetics / tau Proteins - metabolism / Tauopathies - genetics / Tauopathies - metabolism / Translation