Bhagat R, Minaya MA, Renganathan A, Mehra M, Marsh J, Martinez R, Eteleeb AM, Nana AL, Spina S, Seeley WW, Grinberg LT, Karch CM. Long non-coding RNA SNHG8 drives stress granule formation in tauopathies. Mol Psychiatry. 2023 Nov;28(11):4889-4901. Epub 2023 Sep 21 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is is a very elegant study with very interesting results. First I want to note the elegant design of this study. Bhagat and colleagues examine lncRNAs among multiple iPSC lines harboring exon 10 mutations and identify a series of lncRNAs that show consistent changes (reduction) with mutations. They then extend the results to examine iPSC lines with other tau mutations and observe that the lncRNA SNHG8 is consistently reduced in all of the lines. They show that SNHG8 is also reduced in human tauopathies. Finally, increasing SNHG8 reduces stress granule levels. All of this data convincingly shows a strong bidirectional link between the pathophysiology of tau and SNHG8.

    This work is important for multiple reasons. First, it identifies a lncRNA that is directly regulated by tau. Second, it highlights involvement of a specific lncRNA in the pathophysiology of tauopathies, and suggests dysfunction of this pathway occurs early in the pathophysiology of tauopathies. This manuscript certainly feeds into the increasing interest in understanding the role of noncoding RNAs in the pathophysiology of ADRD. The manuscript also expands the literature suggesting that tau functions in part to regulate RNA metabolism, and in the case of SNHG8, a specific RNA species.

    Many studies now show that tau interacts, both directly and indirectly, with RNA.  In the 1990s, the Mandelkow laboratory showed that RNA promotes tau aggregation (Friedhoff et al., 1998). Multiple groups have now shown that RNA promotes tau liquid-liquid phase separation (Zhang et al., 2017; Wegmann et al., 2018; Ash et al, 2021). More recently, the Kraemer group has developed an antibody that recognizes tau-RNA complexes, and they observe that the antibody exhibits a distribution pattern similar to that of the TOMA series tau oligomer antibodies developed by the Kayed group (McMillan et al., 2023; Castillo-Carranza et al., 2014; Ruan et al., 2021; Sengupta et al., 2018). 

    In parallel work, to explore physiological interactions between tau and RNA, my lab showed that tau regulates RNA metabolism by interacting with RNA binding proteins to form stress granules (Wolozin and Ivanov, 2019; Vanderweyde et al., 2016; Jiang et al., 2021). TIA1 has been one of the RNA binding proteins exhibiting strong colocalization with pathologically phosphorylated as well as oligomerized tau. The work by Bhagat and colleagues fits nicely with this work, showing the colocalization of tau, TIA1 and SNHG8 in stress granules.

    More recently, we used optogenetics and an unbiased proteomic screen to show that oligomeric tau interacts most abundantly with the RNA binding protein HNRNPA2B1, stimulating the translational stress response (Jiang et al., 2021). The Abisambra group has shown that phosphorylated tau interacts directly with ribosomes to regulate protein synthesis (Koren et al., 2020; Koren et al., 2019). Conversely, Wang and Jurgasia’s groups recently showed that G3BP2 interacts selectively with monomeric tau and acts as a break on aggregation and tau-mediated stress granule formation (Wang et al., 2023). All of this data suggests that hyperphosphorylated tau has a normal biological function that is independent of microtubule stabilization. This function is to regulate RNA metabolism. Finally, tau likely has other biological functions. For instance, the Parker group has shown that tau acts in the nucleus interacting with nuclear speckles (Lester et al., 2021). 

    Pathological phosphorylation of tau was probably not designed by nature with the goal of giving neuropathologists a biomarker to investigate. It seems more likely that the phosphorylation of tau that we consider pathological actually has a normal biological function, but perhaps this function goes awry in tauopathies. The research described above suggests that one important biological function of pathologically phosphorylated tau is to regulate the translational stress response. Since phosphorylated tau oligomerizes rapidly we can extend this idea to assume that the phosphorylated tau involved in the translational stress response is also oligomeric. Chronic stress goes in tandem with chronic disease. Thus, it is easy to imagine that persistent activation of this pathway is deleterious, much like high blood pressure is necessary for exertion, but chronic high blood causes disease.

    Our understanding of the biology of these pathways, though, continues to evolve. The current manuscript by Bhagat et al. now extends the Tau, TIA1, stress granule pathway to include the lncRNA, SNHG8.  The exact function of SNHG8, though, remains to be determined. Since many lncRNAs also function in the nucleus, interacting with nuclear speckles, this fascinating lncRNA pathway might integrate cytoplasmic and nuclear functions of tau, and also integrate all of this with the pathophysiology of tauopathies.

    References:

    Friedhoff P, Schneider A, Mandelkow EM, Mandelkow E. Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution. Biochemistry. 1998 Jul 14;37(28):10223-30. PubMed.

    Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS, Han S. RNA stores tau reversibly in complex coacervates. PLoS Biol. 2017 Jul;15(7):e2002183. Epub 2017 Jul 6 PubMed.

    Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D, Kamath T, Commins C, Vanderburg C, Roe AD, Fan Z, Molliex AM, Hernandez-Vega A, Muller D, Hyman AA, Mandelkow E, Taylor JP, Hyman BT. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J. 2018 Apr 3;37(7) Epub 2018 Feb 22 PubMed.

    Ash PE, Lei S, Shattuck J, Boudeau S, Carlomagno Y, Medalla M, Mashimo BL, Socorro G, Al-Mohanna LF, Jiang L, Öztürk MM, Knobel M, Ivanov P, Petrucelli L, Wegmann S, Kanaan NM, Wolozin B. TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau. Proc Natl Acad Sci U S A. 2021 Mar 2;118(9) PubMed.

    McMillan PJ, Benbow SJ, Uhrich R, Saxton A, Baum M, Strovas T, Wheeler JM, Baker J, Liachko NF, Keene CD, Latimer CS, Kraemer BC. Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change. Brain. 2023 Aug 1;146(8):3206-3220. PubMed.

    Castillo-Carranza DL, Sengupta U, Guerrero-Muñoz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, Estes DM, Barrett AD, Dineley KT, Jackson GR, Kayed R. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014 Mar 19;34(12):4260-72. PubMed.

    Ruan Z, Pathak D, Venkatesan Kalavai S, Yoshii-Kitahara A, Muraoka S, Bhatt N, Takamatsu-Yukawa K, Hu J, Wang Y, Hersh S, Ericsson M, Gorantla S, Gendelman HE, Kayed R, Ikezu S, Luebke JI, Ikezu T. Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2021 Feb 12;144(1):288-309. PubMed. Correction.

    Sengupta U, Carretero-Murillo M, Kayed R. Preparation and Characterization of Tau Oligomer Strains. Methods Mol Biol. 2018;1779:113-146. PubMed.

    Wolozin B, Ivanov P. Stress granules and neurodegeneration. Nat Rev Neurosci. 2019 Nov;20(11):649-666. Epub 2019 Oct 3 PubMed.

    Vanderweyde T, Apicco DJ, Youmans-Kidder K, Ash PE, Cook C, Lummertz da Rocha E, Jansen-West K, Frame AA, Citro A, Leszyk JD, Ivanov P, Abisambra JF, Steffen M, Li H, Petrucelli L, Wolozin B. Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity. Cell Rep. 2016 May 17;15(7):1455-1466. Epub 2016 May 6 PubMed.

    Jiang L, Lin W, Zhang C, Ash PE, Verma M, Kwan J, van Vliet E, Yang Z, Cruz AL, Boudeau S, Maziuk BF, Lei S, Song J, Alvarez VE, Hovde S, Abisambra JF, Kuo MH, Kanaan N, Murray ME, Crary JF, Zhao J, Cheng JX, Petrucelli L, Li H, Emili A, Wolozin B. Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy. Mol Cell. 2021 Oct 21;81(20):4209-4227.e12. Epub 2021 Aug 27 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.

    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.

    Wang C, Terrigno M, Li J, Distler T, Pandya NJ, Ebeling M, Tyanova S, Hoozemans JJ, Dijkstra AA, Fuchs L, Xiang S, Bonni A, Grüninger F, Jagasia R. Increased G3BP2-Tau interaction in tauopathies is a natural defense against Tau aggregation. Neuron. 2023 Sep 6;111(17):2660-2674.e9. Epub 2023 Jun 28 PubMed.

    Lester E, Ooi FK, Bakkar N, Ayers J, Woerman AL, Wheeler J, Bowser R, Carlson GA, Prusiner SB, Parker R. Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components. Neuron. 2021 May 19;109(10):1675-1691.e9. Epub 2021 Apr 12 PubMed.

    View all comments by Benjamin Wolozin

  2. This is a really thorough write-up of an exciting finding.

    View all comments by Kumar Sambamurti

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Missing ‘Lnc’? Long Noncoding RNAs Bind Tau, Tame Stress Granules