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.

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  1. This report by Wang et al. extends a research trajectory that has tied tau to RNA-binding proteins. The paper focuses on an interaction between tau and the RNA-binding protein coded by the G3BP2 gene, known as Ras GTPase-activating protein-binding protein 2, which was first reported in tau affinity capture eluates of formaldehyde cross-linked SH-SY5Y cells (Gunawardana et al., 2015) and more recently corroborated in an APEX-based tau interactome study (Tracy et al., 2022). The current study establishes through surface plasmon resonance and NMR analyses that the interface of this protein-protein interaction centers on the N-terminal NTF2-like domain within the G3BP2 gene product and R2-R3 repeats within the tau-microtubule-binding domain. When the authors manipulated Ras GTPase-activating protein-binding protein 2 levels and monitored tau seeding and phosphorylation, the G3BP2 gene product emerged as a protective factor that may slow tau aggregation and downstream pathology.

    The authors are to be commended for their intuition to pursue this interaction further. In one aspect the study diverges from our previous data: Our work had pointed toward a broad ability of tau to interact with proteins that harbor RNA recognition motif (RRM) domains—with 27 such proteins co-immunoprecipitating with tau, including proteins coded by the G3BP2 and G3BP1 genes (Gunawardana et al., 2015). Contrasting these earlier results, the authors stressed that the G3BP1 protein did not bind to tau in their human neuronal paradigm. Interestingly, the interaction also does not appear to rely on the RRM domain, indicating that the strong enrichment of RRM-containing proteins in tau interactome datasets may not be explained by a promiscuous tau recognition of these domains themselves but may rely on other shared features amongst proteins that harbor this domain. Finally, the authors suggest that the tau interaction may also be remarkable, relative to the interaction with other stress granule proteins, by being restricted to the soma and being undetectable in the insoluble fraction late in the disease.

    Regardless of where this work will lead—and we are sure to stay tuned—we share the view that this group of RNA-binding proteins deserves further scrutiny as possible targets for therapeutic interventions for the treatment of tauopathies.

    References:

    Gunawardana CG, Mehrabian M, Wang X, Mueller I, Lubambo IB, Jonkman JE, Wang H, Schmitt-Ulms G. The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome. Mol Cell Proteomics. 2015 Nov;14(11):3000-14. Epub 2015 Aug 11 PubMed.

    Tracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, Ward ME, Stevenson E, Hüttenhain R, Kauwe G, Mercedes M, Sweetland-Martin L, Chen X, Mok SA, Wong MY, Telpoukhovskaia M, Min SW, Wang C, Sohn PD, Martin J, Zhou Y, Luo W, Trojanowski JQ, Lee VM, Gong S, Manfredi G, Coppola G, Krogan NJ, Geschwind DH, Gan L. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022 Feb 17;185(4):712-728.e14. Epub 2022 Jan 20 PubMed.

    View all comments by Gerold Schmitt-Ulms

  2. Wang, et al. confirm the association of G3BP2 and tau, and they present evidence to suggest that this partnership mitigates tau tangle formation. The Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative diseaseproximity of the interaction was initially described by Li Gan’s group (Tracy et al., 2021); however, Wang et al. describe in iPSC-derived neurons, organoids, and postmortem human tissues, intricate details about this partnership. The article presents compelling evidence that G3BP2 masks areas of tau that have high affinity for RNA. In doing so, the authors suggest that G3BP2 prevents tau aggregation into mature tangles. Therefore, there is a possibility that G3BP2 may play a critical role in non-pathological tau accumulation.

    In a broader perspective, the findings further cement the emerging concept that tau performs biological functions that extend beyond microtubule stabilization. The tau interactomes, defined by several research teams (including the Wisniewski, Drummond, Wolozin, Seyfried, Gan, and our own lab), identified a conspicuous number of RBPs, which were further characterized by labs including the Kraemer, Parker, and Kayed groups. Here, Wang et al show functional consequences that align with findings from more recent discoveries on how tau/RNA/RBP interactions impact fundamental biological processes such as translation (Koren et al., 2019; Evans et al., 2021).

    Important points to consider include that evidence of G3BP2 association with pathological tau was limited to specific phospho-tau species (AT8). Given work by the Golde lab showing that tangle constitution is dynamic, there is the potential that equilibrium of tau aggregates may shift depending on the association with RBPs such as TIA1, SRRM2, MSUT1, Musashi, and G3BP2, among others. Importantly, modifying G3BP2 levels had a significant impact on tau aggregation. Defining the order and stability of the aggregates would provide much needed information to better understand the toxic properties of the aggregates during the progression of disease, and whether this toxicity can be mitigated.

    References:

    Tracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, Ward ME, Stevenson E, Hüttenhain R, Kauwe G, Mercedes M, Sweetland-Martin L, Chen X, Mok SA, Wong MY, Telpoukhovskaia M, Min SW, Wang C, Sohn PD, Martin J, Zhou Y, Luo W, Trojanowski JQ, Lee VM, Gong S, Manfredi G, Coppola G, Krogan NJ, Geschwind DH, Gan L. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022 Feb 17;185(4):712-728.e14. Epub 2022 Jan 20 PubMed.

    Evans HT, Taylor D, Kneynsberg A, Bodea LG, Götz J. Altered ribosomal function and protein synthesis caused by tau. Acta Neuropathol Commun. 2021 Jun 19;9(1):110. PubMed.

    View all comments by Jose Abisambra

  3. This is a lovely article that complements so much of the work on tau. G3BP is the classic initiator for stress granules and is commonly studied in this context.  It works great in studies of dividing cells. Indeed, G3BP is known to bind TDP-43, and associates with it in stress granule (Aulas et al., 2012; Dammer et al., 2012; McDonald et al., 2011). Many thought that inhibiting G3BP would therefore be a great candidate for knocking down to inhibit TDP-43 pathology in the brain. So far inhibiting G3BP has not yielded strong success, although with the advent of the paper from Wang and Jurgasia’s groups new strategies will certainly appear.

    G3BP1 is ubiquitously and abundantly expressed. One of the really striking aspects of this article is the focus on G3BP2, which is selectively elevated levels of G3BP2 in neurons. This observation highlights the unique biology of RNA binding proteins in neurons. It also suggests a neuronal selective function for G3BP2, one of which appears to be binding to monomeric tau.

    I have always been surprised by the relative paucity of G3BP that we find associated with tau pathology. In our original manuscript on tau and RNA binding proteins we observed that G3BP labeling was elevated in AD and FTD, but surprisingly did not co-localize with tau pathology (Vanderweyde et al., 2012). 

    Our studies of tau liquid-liquid phase separation also compared the actions of TIA1 and G3BP1, and saw a much stronger effect of TIA1, however, clearly it is important to revisit this question examining both G3BP1 and 2 (Ash et al., 2021). Later we selectively isolated tau oligomers, performed proteomics and again did not observe G3BP, although ATXN2 (an interaction partner with G3BP) did show up (Jiang et al., 2021). 

    The manuscript from Wang and Jurgasia’s groups demonstrates first that it is G3BP2 (not G3BP1) that associates with tau and, second, that a potential reason G3BP2 is not found with tau pathology is that is associates with monomeric tau. In a sense, G3BP2 is the counter-lever to HNRNPA2B1 (and TIA1, and perhaps other RNA binding proteins) which preferentially bind to oligomeric tau.

    The biology of this interaction also fits really nicely with the evolving biology of tau protein. Upon identifying HNRNPA2B1 as a partner of oligomeric tau, our attention was immediately drawn to RNA modifications. The reason is that HNRNPA2B1 preferentially associates with RNA that is methylated at N6-methyl adenosine (m6A) positions. Interestingly, G3BP is repelled by m6A labeled RNA (Arguello et al., 2017). The attraction of oligomeric tau to m6A contrasted by the repulsion of G3BP fits nicely with the apparent orthogonal actions of these proteins in tau biology.

    Altogether, this points to a very strong complimentary control over the biology of tau aggregation by RNA binding proteins. If we imagine that phosphorylation and oligomerization of tau functions in part to control protein synthesis, as suggested by Abisambra’s work, then it is easy to imagine that G3BP2 functions in the same axis, perhaps to tamp down the tendency of the stress response to reduce proteins synthesis (Koren et al., 2019).

     Very cool stuff!

    References:

    Aulas A, Stabile S, Vande Velde C. Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP. Mol Neurodegener. 2012 Oct 24;7:54. PubMed.

    Dammer EB, Fallini C, Gozal YM, Duong DM, Rossoll W, Xu P, Lah JJ, Levey AI, Peng J, Bassell GJ, Seyfried NT. Coaggregation of RNA-binding proteins in a model of TDP-43 proteinopathy with selective RGG motif methylation and a role for RRM1 ubiquitination. PLoS One. 2012;7(6):e38658. PubMed.

    McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W, Rouleau GA, Vande Velde C. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet. 2011 Apr 1;20(7):1400-10. PubMed.

    Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A, Ikezu T, Duff K, Wolozin B. Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci. 2012 Jun 13;32(24):8270-83. 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.

    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.

    Arguello AE, DeLiberto AN, Kleiner RE. RNA Chemical Proteomics Reveals the N6-Methyladenosine (m6A)-Regulated Protein-RNA Interactome. J Am Chem Soc. 2017 Dec 6;139(48):17249-17252. Epub 2017 Nov 20 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.

    View all comments by Benjamin Wolozin

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