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.

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  1. The presence of tau has been noted in the nucleus for years, although the focus on cytoplasmic tau has biased the field away from the idea that tau might have a nuclear function (Maina et al., 2018; Mansuroglu et al., 2016). Under basal conditions, non-phosphorylated 2N4R tau localizes to the nucleolus, where it presumably contributes to ribosomal genesis and maturation (Maina et al., 2018). Upon stress, nuclear tau gets phosphorylated and mislocalizes out of the nucleolus and spreads throughout the nucleus. The actions of the dispersed nuclear tau have been largely an enigma beyond the general idea that it associates with chromatin, although many different targets of tau action in the nucleus have been identified (Frost et al., 2016; Wheeler et al., 2019; Younas et al., 2020; Cornelison et al., 2019; Eftekharzadeh et al., 2018; Guo et al., 2018). 

    This current work by Lester et al., emanating from Roy Parker’s laboratory, presents a new take on the actions of “extra-nucleolar” nuclear tau. This work identifies tau alteration of nuclear speckles as a feature of tau aggregation that may contribute to the pathology of tau aggregates. Lester et al. use a tau-seeding model, beginning with HEK 293 reporter cells. The group then identified transcripts that were possibly binding to tau, and discovered many small nuclear and small nucleolar RNAs (snRNAs and snoRNAs). Literature suggests that snRNA associates with a number of nuclear RNA-binding proteins, including MSUT2, SRRM2 and SFPQ, all of which have been shown previously to exhibit abnormal nuclear distribution in Alzheimer brain (Wheeler et al., 2019; Younas et al., 2020; Ke et al., 2012; Tanaka et al., 2018). These proteins are associated with nuclear speckles, which are phase separated droplets.

    The Parker group then explored whether the mislocalized tau alters the dynamic nature of the nuclear speckles using FRAP, showing that speckles containing tau were much more static. This suggests an alteration of function. Finally, since studying HEK 293 cells presents a dubious starting point for tau biology, the group looked in a Tg2541 mouse model and in a couple of cases of Alzheimer’s disease or FTLD brain. The group observed redistribution of SRRM2 in the brains of these cases.

    The study makes important contributions by confirming the existence of RNA in the complex of tau aggregates, and extends the work with discovery of the co-localization and enrichment of tau aggregates with snRNA and snoRNA in the nucleus and nucleoli speckles. These two important and solid findings open up new windows for further exploration of the function and dynamics of tau in nucleus. These findings build on increasing evidence that tau pathology can impact on nuclear function. 

    This interesting manuscript continues emerging work demonstrating intimate involvement of tau with RNA and DNA metabolism, and also how tau modulates phase-separation biology (Zhang et al., 2017; Wegmann et al., 2018; Ash et al., 2021; Wolozin and Ivanov, 2019). The manuscript suffers, though, because it begins with HEK 293 cells rather than neurons, particularly central nervous system neurons. The behavior of tau in peripheral cells differs greatly from that in neurons. Starting with HEK 293 cells likely means that the group missed an extensive amount of biology, and might even have gotten some of the dynamic biology wrong . Despite these caveats, this article adds strong evidence to steadily growing body of work showing that tau impacts nuclear function.

    The following questions are important to investigate in the future studies:

    1. The field needs to uncover how aggregates of tau transport from the cytosol into the nucleus and how the snRNA and snoRNA or nucleoli speckle proteins such as SRRM2 mislocalize into cytosol. Recently, numerous studies have reported that nuclear transport deficits are a predominant feature in tau-related neurodegenerative diseases (Eftekharzadeh et al., 2018; Sheffield et al., 2006). Nuclear envelop disruption and nuclear pore complex dysfunction occurs in parallel with tau aggregation (Frost et al., 2016; Diez and Wegmann, 2020). Whether this mis-localization of tau in the nucleus links to nuclear membrane disruption remains an open question.

    2. The manuscript leaves unanswered the question of whether the snRNA/snoRNA recruitment in tau aggregates has functional consequences on gene expression. A prior study by Beth Frost and Mel Feany found that tau promotes neurodegeneration through global chromatin relaxation (Frost et al., 2014). Whether the binding of tau with snRNA/snoRNA contributes to the chromatin abnormalities and related neuronal toxicity needs further demonstration.

    3. Finally, the authors have demonstrated the co-localization of snRNA/snoRNA and SRRM2 with p-tau in different tauopathy-related disease including AD, FTLD, and CBD. This sequestration of RNAs and RNA-binding proteins into pathologic aggregates may represent a shared pathophysiological feature across multiple degenerative diseases affecting diverse tissue types, with a common feature being depletion of critical RNA processing factors from the nucleus, leading to changes in RNA processing and gene expression. Such a finding raises the possibility that the affected RNA populations are distinct in different tauopathies, which could be relevant to the differential diagnosis of among tauopathies.

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    Maina MB, Bailey LJ, Wagih S, Biasetti L, Pollack SJ, Quinn JP, Thorpe JR, Doherty AJ, Serpell LC. The involvement of tau in nucleolar transcription and the stress response. Acta Neuropathol Commun. 2018 Jul 31;6(1):70. PubMed.

    Mansuroglu Z, Benhelli-Mokrani H, Marcato V, Sultan A, Violet M, Chauderlier A, Delattre L, Loyens A, Talahari S, Bégard S, Nesslany F, Colin M, Souès S, Lefebvre B, Buée L, Galas MC, Bonnefoy E. Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin. Sci Rep. 2016 Sep 8;6:33047. PubMed.

    Frost B, Bardai FH, Feany MB. Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol. 2016 Jan 11;26(1):129-36. Epub 2015 Dec 24 PubMed.

    Wheeler JM, McMillan P, Strovas TJ, Liachko NF, Amlie-Wolf A, Kow RL, Klein RL, Szot P, Robinson L, Guthrie C, Saxton A, Kanaan NM, Raskind M, Peskind E, Trojanowski JQ, Lee VM, Wang LS, Keene CD, Bird T, Schellenberg GD, Kraemer B. Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain. Sci Transl Med. 2019 Dec 18;11(523) PubMed.

    Younas N, Zafar S, Shafiq M, Noor A, Siegert A, Arora AS, Galkin A, Zafar A, Schmitz M, Stadelmann C, Andreoletti O, Ferrer I, Zerr I. SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer's disease. Acta Neuropathol. 2020 Sep;140(3):317-339. Epub 2020 Jun 23 PubMed.

    Cornelison GL, Levy SA, Jenson T, Frost B. Tau-induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila. Aging Cell. 2019 Feb;18(1):e12847. Epub 2018 Nov 9 PubMed.

    Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburg CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RY, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron. 2018 Sep 5;99(5):925-940.e7. PubMed.

    Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA, De Jager PL, Liu Z, Shulman JM. Tau Activates Transposable Elements in Alzheimer's Disease. Cell Rep. 2018 Jun 5;23(10):2874-2880. PubMed.

    Ke Y, Dramiga J, Schütz U, Kril JJ, Ittner LM, Schröder H, Götz J. Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease. PLoS One. 2012;7(4):e35678. PubMed.

    Tanaka H, Kondo K, Chen X, Homma H, Tagawa K, Kerever A, Aoki S, Saito T, Saido T, Muramatsu SI, Fujita K, Okazawa H. The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology. Mol Psychiatry. 2018 Oct;23(10):2090-2110. Epub 2018 Oct 3 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.

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

    Sheffield LG, Miskiewicz HB, Tannenbaum LB, Mirra SS. Nuclear pore complex proteins in Alzheimer disease. J Neuropathol Exp Neurol. 2006 Jan;65(1):45-54. PubMed.

    Diez L, Wegmann S. Nuclear Transport Deficits in Tau-Related Neurodegenerative Diseases. Front Neurol. 2020;11:1056. Epub 2020 Sep 25 PubMed.

    Frost B, Hemberg M, Lewis J, Feany MB. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. 2014 Mar;17(3):357-66. Epub 2014 Jan 26 PubMed.

    View all comments by LULU JIANG

  2. This lovely study from the Parker lab further implicates tau as a splicing disruptor and identifies RNAs that are sequestered within tau aggregates (Raj et al., 2018; Apicco et al., 2019; Hsieh et al., 2019). 

    While the mechanistic aspect of the paper focuses on splicing, the discovery that mRNAs associated with calcium signaling, histones, and transposable elements are enriched in tau aggregates is quite intriguing. Studies ranging from flies to humans, report that calcium signaling, genomic packaging, and transposable elements are dysregulated in tauopathy and that such dysregulation causally mediates neuronal death. Combined with studies from Songi Han’s laboratory, the data presented here by Lester and colleagues opens new doors for future investigation into the role of physiological and pathological tau on RNA metabolism and consequent changes to cellular function and neurotoxicity (Zhang et al., 2017). 

    References:

    Raj T, Li YI, Wong G, Humphrey J, Wang M, Ramdhani S, Wang YC, Ng B, Gupta I, Haroutunian V, Schadt EE, Young-Pearse T, Mostafavi S, Zhang B, Sklar P, Bennett DA, De Jager PL. Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility. Nat Genet. 2018 Nov;50(11):1584-1592. Epub 2018 Oct 8 PubMed.

    Apicco DJ, Zhang C, Maziuk B, Jiang L, Ballance HI, Boudeau S, Ung C, Li H, Wolozin B. Dysregulation of RNA Splicing in Tauopathies. Cell Rep. 2019 Dec 24;29(13):4377-4388.e4. PubMed.

    Hsieh YC, Guo C, Yalamanchili HK, Abreha M, Al-Ouran R, Li Y, Dammer EB, Lah JJ, Levey AI, Bennett DA, De Jager PL, Seyfried NT, Liu Z, Shulman JM. Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease. Cell Rep. 2019 Oct 8;29(2):301-316.e10. 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.

    View all comments by Bess Frost

  3. This interesting work adds to a growing number of reports that tau can co-aggregate with RNA and RNA-binding proteins. Lester and colleagues further show that this leads to disruptions in nuclear compartments, such as speckles, that have critical roles in mRNA splicing, and therefore, cellular maintenance.

    The nucleus is emerging as a major cellular target for tau toxicity, with prior work also establishing that tau dysregulates the nuclear lamin and chromatin domains (Frost et al., 2014; Frost et al., 2016). Is this multipronged nuclear assault by tau connected, and which derangements contribute to tau-mediated neurodegeneration, versus potential downstream consequences? Fruit-fly models expressing human tau may provide some clues, since genetic manipulation of chromatin regulators or nuclear lamins—as well as core spliceosome factors—similarly modify neurodegeneration as shown by Frost et al. and our group (Hsieh et al., 2019). 

    It will be important to understand the timing, mechanisms, and importance of tau-mediated nuclear changes relative to other cellular targets in tauopathies—these insights may guide “nuclear medicine” for Alzheimer’s disease in the near future.

    References:

    Frost B, Hemberg M, Lewis J, Feany MB. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. 2014 Mar;17(3):357-66. Epub 2014 Jan 26 PubMed.

    Frost B, Bardai FH, Feany MB. Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol. 2016 Jan 11;26(1):129-36. Epub 2015 Dec 24 PubMed.

    Hsieh YC, Guo C, Yalamanchili HK, Abreha M, Al-Ouran R, Li Y, Dammer EB, Lah JJ, Levey AI, Bennett DA, De Jager PL, Seyfried NT, Liu Z, Shulman JM. Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease. Cell Rep. 2019 Oct 8;29(2):301-316.e10. PubMed.

    View all comments by Joshua Shulman

  4. Tau aggregates are a “sponge” for numerous biological molecules, including heparan sulfate, proteins, lipids, and nucleic acids such as RNAs. A fundamental question is whether any of these molecules are primary causes of disease by participating in tau seeding and spreading or if they are secondary causes because their sequestration in tau aggregates results in a gain or a loss of function (Galas et al., 2019). 

    In frontotemporal lobar degeneration, mis-processing and mis-sorting of RNAs contribute to disease. In rare muscular disorders, such as myotonic dystrophy, a mis-splicing of RNAs targeted by the muscleblind-like protein family reduces the diversity of tau isoforms leading to tau aggregation in adults (Fernandez-Gomez et al., 2019; Goodwin et al., 2015; Caillet-Boudin et al., 2014). RNA metabolism and splicing can, therefore, contribute to neurodegenerative disorders, however, the mechanism remains ill-defined.

    Here, Evan Lester and colleagues have shown that tau aggregates interfere with different nuclear factors and functions. Tau aggregates from several cellular and animal models were isolated from the cytosol or from nuclei then accompanying RNAs and proteins were identified using orthogonal omics methods. Aggregates were shown to be enriched in poly-A RNA, snoRNAs (U3, U17, and U8), snRNAs (U2 and U1), and some mRNAs coding for nuclear, splicing, and channel proteins. The presence of U1 snRNP is confirmatory of previous data (Bai et al., 2013; Zhu et al., 2020). Characterization of nuclear tau aggregates is novel and they were shown herein to co-localize with the speckle splicing protein SRRM2 and with other speckle components/splicing factors. Moreover, a pathological epitope of tau (phosphorylated at Thr205 and Ser422) co-stained with SRRM2, speckles, and poly(A) RNAs together, helping to demonstrate that tau aggregates are found in the nucleus, localize with speckles, and contain speckle proteins such as SSRM2 and several RNAs.

    Interestingly, SRRM2 was also associated with cytosolic tau aggregates, which deplete SSRM2, along with some of its partners such as PNN, SFPQ, and DYRK1A, from nuclear speckles. Does the presence of SRRM2 speckle-associated protein partners in nuclear and cytosolic tau aggregates modify the properties of nuclear speckles and thus mRNA splicing? The authors addressed this question, showing that in cells with tau aggregates several mis-splicing events, especially the retention of more than 1,200 introns encoded by 641 genes, correlated with altered speckle properties, such as their dynamics and spatial organization. Even if many of the components found in tau aggregates were identified in HEK cells (using a FRET cell assay developed by Marc Diamond group), Lester and collaborators validated their findings in human brains. In fact, the loss of nuclear SRRM2 staining was shown to occur in several neurodegenerative diseases, including corticobasal degeneration, Alzheimer’s disease, and frontotemporal lobar degeneration, suggesting a common mechanism associated with tauopathies.

    Defective deoxyribo- and ribostasis should now be considered as a consequence of tau aggregation. Tau may protect nucleic acids from stress, whereas in contrast, pathological tau aggregates lead to the defective stasis of nuclear and cytosolic RNAs, the consequences of which remain to be fully characterized. Lester and collaborators make a major contribution toward this better understanding.

    References:

    Galas MC, Bonnefoy E, Buee L, Lefebvre B. Emerging Connections Between Tau and Nucleic Acids. Adv Exp Med Biol. 2019;1184:135-143. PubMed.

    Fernandez-Gomez F, Tran H, Dhaenens CM, Caillet-Boudin ML, Schraen-Maschke S, Blum D, Sablonnière B, Buée-Scherrer V, Buee L, Sergeant N. Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy?. Adv Exp Med Biol. 2019;1184:207-216. PubMed.

    Goodwin M, Mohan A, Batra R, Lee KY, Charizanis K, Fernández Gómez FJ, Eddarkaoui S, Sergeant N, Buée L, Kimura T, Clark HB, Dalton J, Takamura K, Weyn-Vanhentenryck SM, Zhang C, Reid T, Ranum LP, Day JW, Swanson MS. MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain. Cell Rep. 2015 Aug 18;12(7):1159-68. Epub 2015 Aug 6 PubMed.

    Caillet-Boudin ML, Fernandez-Gomez FJ, Tran H, Dhaenens CM, Buee L, Sergeant N. Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy. Front Mol Neurosci. 2014 Jan 9;6:57. PubMed.

    Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, Wang X, Xia Q, Duong DM, Street C, Cantero G, Cheng D, Jones DR, Wu Z, Li Y, Diner I, Heilman CJ, Rees HD, Wu H, Lin L, Szulwach KE, Gearing M, Mufson EJ, Bennett DA, Montine TJ, Seyfried NT, Wingo TS, Sun YE, Jin P, Hanfelt J, Willcock DM, Levey A, Lah JJ, Peng J. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16562-7. PubMed.

    Zhu W, Wei X, Wang Y, Li J, Peng L, Zhang K, Bai B. Effects of U1 Small Nuclear Ribonucleoprotein Inhibition on the Expression of Genes Involved in Alzheimer's Disease. ACS Omega. 2020 Oct 6;5(39):25306-25311. Epub 2020 Sep 23 PubMed.

    View all comments by Luc Buee

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