Simone R, Javad F, Emmett W, Wilkins OG, Almeida FL, Barahona-Torres N, Zareba-Paslawska J, Ehteramyan M, Zuccotti P, Modelska A, Siva K, Virdi GS, Mitchell JS, Harley J, Kay VA, Hondhamuni G, Trabzuni D, Ryten M, Wray S, Preza E, Kia DA, Pittman A, Ferrari R, Manzoni C, Lees A, Hardy JA, Denti MA, Quattrone A, Patani R, Svenningsson P, Warner TT, Plagnol V, Ule J, de Silva R. MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration. Nature. 2021 Jun;594(7861):117-123. Epub 2021 May 19 PubMed.

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  1. This is an eye-popping and elegant study about a novel paradigm of gene expression regulation directly relevant to MAPT/tau.

    MAPT is situated famously on chromosome 17 and here Simone et al. demonstrate that a slightly overlapping transcription unit (MAPT-AS1) is transcriptionally active and can generate untranslated RNAs that can cause altered regulation of MAPT/tau itself. They present data indicating that the MAPT-AS1 locus could be pathogenetically relevant: Higher MAPT-AS1 transcription is associated with lower MAPT/Tau expression, and lower AD-type Braak NFT stages. As further evidence of possible clinical relevance, Parkinson's disease- and progressive supranuclear palsy-associated gene variants are within the MAPT-AS1 gene.

    A mechanism for the MAPT-AS1-mediated regulation of MAPT/tau is proposed, wherein the "embedded inverted" MAPT-AS1 RNA structure binds to a portion of the MAPT RNA transcript to impede MAPT/tau translation, microRNA (miRNA)-style. It is proposed that naturally occurring miRNAs in antisense transcripts ("MIR-NATS") are indeed a widespread and hitherto underappreciated gene regulatory paradigm with particular relevance to dementia diseases.

    This is a lovely body of work that highlights the merits of looking carefully at important things! Whereas it has long been appreciated that tau protein pathology has an enormous impact on public health, this remains an alarmingly under-studied topic. This particular article provides yet another reminder of the fact that nature loves complexity, and that the human brain is perhaps the greatest demonstration of that principle.

    It remains to be seen if, and how, the MAPT-AS1 genetic lesion can be exploited for diagnostic and/or therapeutic strategies. RNA-based therapeutic strategies for CNS conditions have come a long way—so here's hoping! 

    In summary, I'm impressed and interested to learn more about this type of gene expression regulation, and its translational potential. 

    View all comments by Peter Nelson

  2. In this new paper, the authors use a variety of experimental approaches both in vitro and in vivo to demonstrate that MAPT-AS1, a natural antisense transcript (NAT) enriched in the brain, can bind to tau mRNA and inhibit its translation.

    This is an exciting discovery, because it adds further evidence that RNA metabolism pathways are excellent therapeutic targets in different neurodegenerative diseases, and it raises the possibility that boosting expression of this specific antisense RNA may be a novel therapeutic approach. It also highlights the complexity of RNA biology in health and disease. However, we need to keep in mind that, like miRNAs or antisense oligonucleotides (ASOs), MAPT-AS1 overexpression could have off-target effects that will need to be investigated.

    View all comments by Veroniki Nikolaki

  3. This is a great paper. Tau regulation at the ribosome level is quite a recent idea, pioneered at the protein-protein interaction level by Joe Abisambra in Florida (Maziuk et al., 2018; Koren et al., 2019; Koren et al., 2020). In fact, tau proteins are strongly linked to ribosomes in many publications—if one looks carefully at the data.

    This study describes very important functional aspects of tau mRNA interactions with ribosomal entities, and the regulation of tau mRNA translation. Showing that mammalian-wide interspersed repeat natural antisense transcripts (MIR-NATs) can inhibit mRNA interactions with ribosomal units and rRNA refines our idea of how tau and other proteins are dysregulated in neurodegenerative diseases. Furthermore, the finding that this mechanism is pronounced in neuronal processes adds to our general neurobiological understanding of how local translation of proteins can be regulated in compartments far away from the nucleus, namely dendrites, axon terminals, etc. It will be very interesting to see whether local tau translation is regulated by controlled release of MIR-NATs at sites of translation, and if aberrant somatodendritic tau translation in response to Aβ, as shown by the Mandelkow group (Zempel et al., 2010; Zempel and Mandelkow, 2014), involves repression of tau-targeted MIR-NATs.

    Therapeutically, for tau-related neurodegenerative diseases, the findings open up great new ways for tweaking tau protein expression using a naturally occurring mechanism. Similar to our recently published approach using zinc-finger transcription factors (Wegmann et al., 2021), one could design tau-specific MIR-NATs that, in combination with neuron-specific—maybe even brain region-specific—expression through viral vectors, could repress tau mRNA translation. If MIR-NATs are stable enough, one could also think of an approach similar to antisense oligonucleotides.

    I am very happy to see such a big step forward in the field.

    References:

    Maziuk BF, Apicco DJ, Cruz AL, Jiang L, Ash PE, da Rocha EL, Zhang C, Yu WH, Leszyk J, Abisambra JF, Li H, Wolozin B. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol Commun. 2018 Aug 1;6(1):71. PubMed.

    Koren SA, Hamm MJ, Meier SE, Weiss BE, Nation GK, Chishti EA, Arango JP, Chen J, Zhu H, Blalock EM, Abisambra JF. Tau drives translational selectivity by interacting with ribosomal proteins. Acta Neuropathol. 2019 Apr;137(4):571-583. Epub 2019 Feb 13 PubMed.

    Koren SA, Galvis-Escobar S, Abisambra JF. Tau-mediated dysregulation of RNA: Evidence for a common molecular mechanism of toxicity in frontotemporal dementia and other tauopathies. Neurobiol Dis. 2020 Jul;141:104939. Epub 2020 May 12 PubMed.

    Zempel H, Thies E, Mandelkow E, Mandelkow EM. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci. 2010 Sep 8;30(36):11938-50. PubMed.

    Zempel H, Mandelkow E. Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci. 2014 Dec;37(12):721-32. Epub 2014 Sep 12 PubMed.

    Wegmann S, DeVos SL, Zeitler B, Marlen K, Bennett RE, Perez-Rando M, MacKenzie D, Yu Q, Commins C, Bannon RN, Corjuc BT, Chase A, Diez L, Nguyen HB, Hinkley S, Zhang L, Goodwin A, Ledeboer A, Lam S, Ankoudinova I, Tran H, Scarlott N, Amora R, Surosky R, Miller JC, Robbins AB, Rebar EJ, Urnov FD, Holmes MC, Pooler AM, Riley B, Zhang HS, Hyman BT. Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci Adv. 2021 Mar;7(12) Print 2021 Mar PubMed.

    View all comments by Susanne Wegmann

  4. The microtubule-associated protein tau (MAPT) gene is a major disease locus shown to cause, or increase the risk of, primary tauopathies such as progressive supranuclear palsy and frontotemporal lobar degeneration, as well as common neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease (PD). Better knowledge of the complex regulatory elements involved in MAPT gene expression at stages of transcription, translation, and post-translation would be critical for our understanding of multiple neurodegenerative diseases and potential therapeutics.

    This paper by Simone et al. extends our understanding of the role of natural antisense transcripts (NATS) in the regulation of MAPT gene translation and degradation. The authors’ findings highlight several avenues of future research. Firstly, common variants that fall within the H1/H2 haplotype region could be examined for correlation with expression of MAPT-AS1, rather than MAPT, given that the expression of the former locus appears to be more strongly associated with disease risk. For example, the rs2301689 variant is strongly associated with risk of PD (Witoelar et al., 2017), but is within the MAPT-AS1 locus and not the MAPT gene.

    Further, another issue to be explored is the role of altered alternative splicing, which is an important pathogenic mechanism for the MAPT gene (Hutton et al., 1998). Coupland et al. (2016) correlated MAPT-AS1 with decrease of the four-repeat isoform of tau, rather than alternatively spliced transcripts. One could explore the relationship between alternative splicing and protein translation via MAPT-AS1 (Soergel et al., 2000-2003). 

    Finally, for successful translation of MAPT-AS1 and other NATs as avenues for therapeutic intervention, it would be important to determine the relative benefits of reducing tau protein levels via NAT compared with reducing MAPT transcript levels using established RNAi technologies. Moreover, it would be of interest to determine whether there were behavioral and neuropathological effects associated with AAV9-t-NAT expression in the htau transgenic mouse model the authors used. The recent success of the mRNA-based COVID-19 vaccines have highlighted the feasibility of using RNAs, rather than DNAs, as effector molecules. What is needed now is a concerted effort to design strategies for delivering these NAT molecules into the brain in a safe manner and at therapeutically relevant levels.

    References:

    Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, Blauwendraat C, Thompson WK, Hernandez DG, Djurovic S, Schork AJ, Bettella F, Ellinghaus D, Franke A, Lie BA, McEvoy LK, Karlsen TH, Lesage S, Morris HR, Brice A, Wood NW, Heutink P, Hardy J, Singleton AB, Dale AM, Gasser T, Andreassen OA, Sharma M, International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. JAMA Neurol. 2017 Jul 1;74(7):780-792. PubMed.

    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.

    Coupland KG, Kim WS, Halliday GM, Hallupp M, Dobson-Stone C, Kwok JB. Role of the Long Non-Coding RNA MAPT-AS1 in Regulation of Microtubule Associated Protein Tau (MAPT) Expression in Parkinson's Disease. PLoS One. 2016;11(6):e0157924. Epub 2016 Jun 23 PubMed.

    Soergel DA, Lareau LF, Brenner SE. Regulation of Gene Expression by Coupling of Alternative Splicing and NMD. In: Madame Curie Bioscience Database [Internet]. Austin (TX). Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6088/

    View all comments by John Kwok

  5. Hats off to the authors for illumiNATing NATs.

    Maintaining cellular checks and balances requires multiple mechanisms. A recently reported participant to maintain tau protein homeostasis was mammalian-wide interspersed repeat (MIR) natural antisense transcripts (MIR-NATs). We credit the authors for discovering regulation of MAPT protein expression via MAPT-AS1. This would help us understand the regulation of other AD-related proteins expression. Indeed, their elegant study of the role of NATs in aggregating proteins is an important milestone for the Alzheimer's disease field.

    First, similar-sounding words—MIR and miR—give us pause. Both MIR and microRNA (miR) usually silence protein expression, and both require specific short nucleotide sequences to function. However, MAPT-AS1 is encoded by a multi-kilobase intron-containing gene, while the genes for even the pre-pro-miRNAs are shorter and none so far have been found with introns.

    Also, their respective mechanisms are quite different. MAPT-AS1 interferes with ribosomal RNA binding, while miRNA usually binds 3'-untranslated region (3'-UTR) mRNA and acts as a recognition sequence for the RISC (usually) to destabilize an mRNA. We also note an exception: A novel miR-346 upregulates APP expression via targeting 5'-UTR of APP mRNA (Long et al., 2019). The AD field is never devoid of surprises!

    Returning to MIR, the authors showed functionality and specificity by using human neuroblastoma cells. A similar effect was not observed in mice until human MAPT was knocked in. This is similar to many prior publications, which have shown important differences in gene regulation, such as for APOE, between humans and mice (Maloney et al., 2010; Maloney et al., 2007). One could easily miss the effects of NAT on other genes in mouse AD models, as there are many differences between native and human regulatory elements in humans and mice.

    The authors state that the H1 haplotype of the MAPT gene boosts the risk of tauopathies. We previously characterized the H2 haplotype MAPT promoter (Maloney and Lahiri, 2012). Comparison with human H1 sequences revealed differences in transcription factor sites, DNA-protein interactions, and a hypoxia inducible element in the H2 sequence (Maloney and Lahiri, 2012). Comparison between our H2 sequence and the corresponding ~ 5kb portion of the MAPT-AS1 gene revealed a 1.44 percent difference in homology. Whether this would prove critical for MAPT-AS1 activity in H1 vs. H2 haplotypes would need to be determined.

    Current research on noncoding RNAs, mRNA-UTRs, NATs, and other RNA subjects (e.g., mRNA vaccine) ushers in the beginning of a golden phase of RNA work. As await next-generation RNA therapeutics, we congratulate the fasciNATing work led by Rohan de Silva.

    References:

    Simone R, Javad F, Emmett W, Wilkins OG, Almeida FL, Barahona-Torres N, Zareba-Paslawska J, Ehteramyan M, Zuccotti P, Modelska A, Siva K, Virdi GS, Mitchell JS, Harley J, Kay VA, Hondhamuni G, Trabzuni D, Ryten M, Wray S, Preza E, Kia DA, Pittman A, Ferrari R, Manzoni C, Lees A, Hardy JA, Denti MA, Quattrone A, Patani R, Svenningsson P, Warner TT, Plagnol V, Ule J, de Silva R. MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration. Nature. 2021 Jun;594(7861):117-123. Epub 2021 May 19 PubMed.

    Long JM, Maloney B, Rogers JT, Lahiri DK. Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease. Mol Psychiatry. 2019 Mar;24(3):345-363. Epub 2018 Nov 23 PubMed.

    Maloney B, Ge YW, Petersen RC, Hardy J, Rogers JT, Pérez-Tur J, Lahiri DK. Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions. Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):185-201. PubMed.

    Maloney B, Ge YW, Alley GM, Lahiri DK. Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.

    Maloney B, Lahiri DK. Structural and functional characterization of H2 haplotype MAPT promoter: Unique neurospecific domains and a hypoxia-inducible element would enhance rationally targeted tauopathy research for Alzheimer's disease. Gene. 2012 Jan 30; PubMed.

    View all comments by Bryan Maloney

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This paper appears in the following:

News

  1. MIR-NATs: Noncoding RNAs That Rein in Aggregating Proteins?

Research Models

  1. MAPT(H1.0)-GR
  2. MAPT(H1.0*N279K)-GR
  3. MAPT(H2.1)-GR
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  5. MAPT 10IVS+16 C>T