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.

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration / Simone, R.; Javad, F.; Emmett, W.; Wilkins, O. G.; Almeida, F. L.; Barahona-Torres, N.; Zareba-Paslawska, J.; Ehteramyan, M.; Zuccotti, P.; Modelska, A.; Siva, K.; Virdi, G. S.; Mitchell, J. S.; Harley, J.; Kay, V. A.; Hondhamuni, G.; Trabzuni, D.; Ryten, M.; Wray, S.; Preza, E.; Kia, D. A.; Pittman, A.; Ferrari, R.; Manzoni, C.; Lees, A.; Hardy, J. A.; Denti, M. A.; Quattrone, A.; Patani, R.; Svenningsson, P.; Warner, T. T.; Plagnol, V.; Ule, J.; de Silva, R.. - In: NATURE. - ISSN 0028-0836. - ELETTRONICO. - 594:7861(2021), pp. 117-123. [10.1038/s41586-021-03556-6]

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

Zuccotti P.;Modelska A.;Siva K.;Denti M. A.;Quattrone A.;
2021

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.
7861
Simone, R.; Javad, F.; Emmett, W.; Wilkins, O. G.; Almeida, F. L.; Barahona-Torres, N.; Zareba-Paslawska, J.; Ehteramyan, M.; Zuccotti, P.; Modelska, A.; Siva, K.; Virdi, G. S.; Mitchell, J. S.; Harley, J.; Kay, V. A.; Hondhamuni, G.; Trabzuni, D.; Ryten, M.; Wray, S.; Preza, E.; Kia, D. A.; Pittman, A.; Ferrari, R.; Manzoni, C.; Lees, A.; Hardy, J. A.; Denti, M. A.; Quattrone, A.; Patani, R.; Svenningsson, P.; Warner, T. T.; Plagnol, V.; Ule, J.; de Silva, R.
MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration / Simone, R.; Javad, F.; Emmett, W.; Wilkins, O. G.; Almeida, F. L.; Barahona-Torres, N.; Zareba-Paslawska, J.; Ehteramyan, M.; Zuccotti, P.; Modelska, A.; Siva, K.; Virdi, G. S.; Mitchell, J. S.; Harley, J.; Kay, V. A.; Hondhamuni, G.; Trabzuni, D.; Ryten, M.; Wray, S.; Preza, E.; Kia, D. A.; Pittman, A.; Ferrari, R.; Manzoni, C.; Lees, A.; Hardy, J. A.; Denti, M. A.; Quattrone, A.; Patani, R.; Svenningsson, P.; Warner, T. T.; Plagnol, V.; Ule, J.; de Silva, R.. - In: NATURE. - ISSN 0028-0836. - ELETTRONICO. - 594:7861(2021), pp. 117-123. [10.1038/s41586-021-03556-6]
File in questo prodotto:
File Dimensione Formato  
Simone_Nature_2021_short.pdf

Solo gestori archivio

Descrizione: Articolo principale
Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 3.87 MB
Formato Adobe PDF
3.87 MB Adobe PDF   Visualizza/Apri
Simone2021_2016-04-05263D_text-Figures_final (1).pdf

accesso aperto

Tipologia: Post-print referato (Refereed author’s manuscript)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 3.07 MB
Formato Adobe PDF
3.07 MB Adobe PDF Visualizza/Apri
EMS126982.pdf

accesso aperto

Tipologia: Pre-print non referato (Non-refereed preprint)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 7.78 MB
Formato Adobe PDF
7.78 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/333606
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 14
social impact