MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration
Authors listRoberto Simone Faiza Javad Warren Emmett Oscar Wilkins Filipa Lourenço Almeida Natalia Barahona-Torres Justyna Zareba-Paslawska Mazdak Ehteramyan Paola Zuccotti Angelika Modelska Kavitha Siva Gurvir Virdi Jamie 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 Rohan de Silva
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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.
Issue number 7861