Tau protein liquid–liquid phase separation can initiate tau aggregation
Open accessAbstract
The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases. The microtubule binding protein tau can undergo liquid‐liquid phase separation under physiological conditions. Phosphorylated, FTD‐mutant, and Alzheimer's disease brain tau is capable of forming droplets that can initiate the formation of aberrant, aggregated tau “seeds”. LLPS may play a role in different tauopathies. An Alzheimer's Disease‐associated tau phase transition from soluble to droplet may exemplify a biophysical mechanism underlying several neurodegenerative diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Classical phase-separating proteins such as FUS, TDP-43, tau, and α-synuclein exhibit abnormal accumulation and aggregation that are closely linked to neuronal dysfunction.
“Classical phase‐separating proteins such as FUS, 46 TDP‐43, 47 tau, 25 , 29 and α‐synuclein 48 exhibit abnormal accumulation and aggregation that are closely linked to neuronal dysfunction.”
From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [29]
LLPS may initiate tau aggregation, and this process is enhanced by tau phosphorylation, and impaired by acetylation.
“LLPS may initiate tau aggregation, and this process is enhanced by tau phosphorylation, and impaired by acetylation [225–227].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [226]
Peptides containing 2N4R tau microtubule binding repeats or full-length tau undergo LLPS in solution and cells, respectively.
“Peptides containing 2N4R tau microtubule binding repeats or and full-length tau undergo LLPS in solution and cells, respectively [225, 226].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [226]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Lodish, H. F. (1986) · Cited by 5,640 · see citing works
Germline P Granules Are Liquid Droplets That Localize by Controlled Dissolution/Condensation
Brangwynne, C. P., Eckmann, C. R., Courson, D. S., Rybarska, A., Hoege, C., Gharakhani, J., Jülicher, F., & Hyman, A. A. (2009) · Science · doi:10.1126/science.1172046 · Cited by 3,215 · see citing works
Self-citationLiquid-Liquid Phase Separation in Biology
Hyman, A. A., Weber, C. A., & Jülicher, F. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100913-013325 · Cited by 3,155 · see citing works
Self-citationZur Lehre von der Wirkung der Salze
Hofmeister, F. (1888) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf01918191 · Cited by 2,969 · see citing works
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation
Patel, A., Lee, H. O., Jawerth, L. M., Maharana, S., Jahnel, M., Hein, M. Y., Stoynov, S., Mahamid, J., Saha, S., Franzmann, T. M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.047 · Cited by 2,927 · see citing works
Self-citationMolliex, A., Temirov, J. P., Lee, J., Coughlin, M., Kanagaraj, A., Kim, H. J., Mittag, T., & Taylor, J. P. (2015) · Cell · doi:10.1016/j.cell.2015.09.015 · Cited by 2,658 · see citing works
Self-citationPhase transitions in the assembly of multivalent signalling proteins
Li, P., Banjade, S., Cheng, H., Kim, S., Chen, B., Guo, L., Llaguno, M. C., Hollingsworth, J. V., King, D., Banani, S. F., et al. (2012) · Nature · doi:10.1038/nature10879 · Cited by 2,565 · see citing works
Intrinsically disordered proteins in cellular signalling and regulation
Wright, P. E., & Dyson, H. J. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3920 · Cited by 2,371 · see citing works
Staging of alzheimer's disease-related neurofibrillary changes
Braak, H., & Braak, E. (1995) · Neurobiology of Aging · doi:10.1016/0197-4580(95)00021-6 · Cited by 2,357 · see citing works
Decoding ALS: from genes to mechanism
Taylor, J. P., Brown, R. H., & Cleveland, D. W. (2016) · Nature · doi:10.1038/nature20413 · Cited by 2,047 · see citing works
Self-citationTau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., et al. (2005) · Science · doi:10.1126/science.1113694 · Cited by 2,014 · see citing works
Self-citationKato, M., Han, T. W., Xie, S., Shi, K., Du, X., Wu, L. C., Mirzaei, H., Goldsmith, E. J., Longgood, J., Pei, J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.017 · Cited by 2,012 · see citing works
Nott, T. J., Petsalaki, E., Farber, P., Jervis, D., Fussner, E., Plochowietz, A., Craggs, T. D., Bazett-Jones, D. P., Pawson, T., Forman-Kay, J. D., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.01.013 · Cited by 1,803 · see citing works
Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins
Lin, Y., Protter, D. S. W., Rosen, M. K., & Parker, R. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.08.018 · Cited by 1,594 · see citing works
Polymer physics of intracellular phase transitions
Brangwynne, C., Tompa, P., & Pappu, R. (2015) · Nature Physics · doi:10.1038/nphys3532 · Cited by 1,415 · see citing works
Intrinsically Disordered Proteins in Human Diseases: Introducing the D 2 Concept
Uversky, V. N., Oldfield, C. J., & Dunker, A. K. (2008) · Annual Review of Biophysics · doi:10.1146/annurev.biophys.37.032807.125924 · Cited by 1,406 · see citing works
Elbaum-Garfinkle, S., Kim, Y., Szczepaniak, K., Chen, C. C.-H., Eckmann, C. R., Myong, S., & Brangwynne, C. P. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504822112 · Cited by 1,278 · see citing works
(1987) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(87)90455-5 · Cited by 1,130 · see citing works
Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.030 · Cited by 1,118 · see citing works
Tau pathology in Alzheimer disease and other tauopathies
Iqbal, K., del C. Alonso, A., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C.-X., Khatoon, S., Li, B., Liu, F., Rahman, A., et al. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.09.008 · Cited by 1,037 · see citing works
Goedert, M., Jakes, R., Spillantini, M. G., Hasegawa, M., Smith, M. J., & Crowther, R. A. (1996) · Nature · doi:10.1038/383550a0 · Cited by 1,036 · see citing works
von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E.-M., & Mandelkow, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.10.5129 · Cited by 1,021 · see citing works
Self-citationAugustinack, J. C., Schneider, A., Mandelkow, E.-M., & Hyman, B. T. (2002) · Acta Neuropathologica · doi:10.1007/s004010100423 · Cited by 998 · see citing works
Self-citationSpatiotemporal Control of Intracellular Phase Transitions Using Light-Activated optoDroplets
Shin, Y., Berry, J. M., Pannucci, N. L., Haataja, M., Toettcher, J. E., & Brangwynne, C. P. (2016) · Cell · doi:10.1016/j.cell.2016.11.054 · Cited by 972 · see citing works
Burke, K. A., Janke, A. M., Rhine, C. L., & Fawzi, N. L. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.006 · Cited by 932 · see citing works
Conicella, A. E., Zerze, G. H., Mittal, J., & Fawzi, N. L. (2016) · Structure · doi:10.1016/j.str.2016.07.007 · Cited by 860 · see citing works
Murakami, T., Qamar, S., Lin, J. Q., Schierle, G. S. K., Rees, E. J., Miyashita, A., Costa, A. R., Dodd, R. B., Chan, F. T. S., Michel, C. H., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.10.030 · Cited by 848 · see citing works
Fulton, A. B. (1982) · Cell · doi:10.1016/0092-8674(82)90231-8 · Cited by 830 · see citing works
Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M. (2017) · Nature Communications · doi:10.1038/s41467-017-00480-0 · Cited by 782 · see citing works
Self-citationPhase separation in biology; functional organization of a higher order
Mitrea, D. M., & Kriwacki, R. W. (2016) · Cell Communication and Signaling · doi:10.1186/s12964-015-0125-7 · Cited by 723 · see citing works
Šimić, G., Leko, M. B., Wray, S., Harrington, C. R., Delalle, I., Milošević, N. J., Bažadona, D., Buée, L., de Silva, R., Giovanni, G. D., et al. (2016) · Biomolecules · doi:10.3390/biom6010006 · Cited by 698 · see citing works
Proteopathic tau seeding predicts tauopathy in vivo
Holmes, B. B., Furman, J. L., Mahan, T. E., Yamasaki, T. R., Mirbaha, H., Eades, W. C., Belaygorod, L., Cairns, N. J., Holtzman, D. M., & Diamond, M. I. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411649111 · Cited by 696 · see citing works
C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles
Lee, K., Zhang, P., Kim, H. J., Mitrea, D. M., Sarkar, M., Freibaum, B. D., Cika, J., Coughlin, M., Messing, J. A., Molliex, A., et al. (2016) · Cell · doi:10.1016/j.cell.2016.10.002 · Cited by 687 · see citing works
Self-citationMonahan, Z. T., Ryan, V. H., Janke, A. M., Burke, K. A., Rhoads, S. N., Zerze, G. H., O’Meally, R. N., Dignon, G. L., Conicella, A. E., Zheng, W., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201696394 · Cited by 685 · see citing works
The Primary Structure and Heterogeneity of Tau Protein from Mouse Brain
Lee, G. S., Cowan, N. J., & Kirschner, M. W. (1988) · Science · doi:10.1126/science.3122323 · Cited by 680 · see citing works
The Neuropathology and Neurobiology of Traumatic Brain Injury
Blennow, K., Hardy, J., & Zetterberg, H. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.021 · Cited by 669 · see citing works
Domains of tau Protein and Interactions with Microtubules
Gustke, N., Trinczek, B., Biernat, J., Mandelkow, E.-M., & Mandelkow, E. (1994) · Biochemistry · doi:10.1021/bi00198a017 · Cited by 655 · see citing works
Self-citationAlberti, S. (2017) · Current Biology · doi:10.1016/j.cub.2017.08.069 · Cited by 654 · see citing works
Structural Polymorphism of 441-Residue Tau at Single Residue Resolution
Mukrasch, M. D., Bibow, S., Korukottu, J., Jeganathan, S., Biernat, J., Griesinger, C., Mandelkow, E., & Zweckstetter, M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000034 · Cited by 652 · see citing works
Self-citationThe tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease
King, O. D., Gitler, A. D., & Shorter, J. (2012) · Brain Research · doi:10.1016/j.brainres.2012.01.016 · Cited by 637 · see citing works
Tau phosphorylation in neuronal cell function and dysfunction
Johnson, G. V. W., & Stoothoff, W. H. (2004) · Journal of Cell Science · doi:10.1242/jcs.01558 · Cited by 624 · see citing works
Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons
Chen, J., Kanai, Y., Cowan, N. J., & Hirokawa, N. (1992) · Nature · doi:10.1038/360674a0 · Cited by 601 · see citing works
von Bergen�, M., Barghorn, S., Li, L., Marx, A., Biernat, J., Mandelkow, E., & Mandelkow�, E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105196200 · Cited by 590 · see citing works
Self-citationNatively Unfolded Nucleoporins Gate Protein Diffusion across the Nuclear Pore Complex
Patel, S. S., Belmont, B. J., Sante, J. M., & Rexach, M. F. (2007) · Cell · doi:10.1016/j.cell.2007.01.044 · Cited by 566 · see citing works
Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E.-M., & Mandelkow, E. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01386-5 · Cited by 548 · see citing works
Self-citationKroschwald, S., Maharana, S., Matějů, D., Malinovska, L., Nüske, E., Poser, I., Richter, D., & Alberti, S. (2015) · eLife · doi:10.7554/elife.06807 · Cited by 545 · see citing works
Caspase activation precedes and leads to tangles
de Calignon, A., Fox, L. M., Pitstick, R., Carlson, G. A., Bacskai, B. J., Spires-Jones, T. L., & Hyman, B. T. (2010) · Nature · doi:10.1038/nature08890 · Cited by 517 · see citing works
Self-citationDrubin, D. G., Feinstein, S. C., Shooter, E. M., & Kirschner, M. W. (1985) · The Journal of Cell Biology · doi:10.1083/jcb.101.5.1799 · Cited by 510 · see citing works
RNA transcription modulates phase transition-driven nuclear body assembly
Berry, J., Weber, S. C., Vaidya, N., Haataja, M., & Brangwynne, C. P. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509317112 · Cited by 501 · see citing works
Wille, H., Drewes, G., Biernat, J., Mandelkow�, E., & Mandelkow�, E. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.118.3.573 · Cited by 477 · see citing works
Self-citationMorris, M., Knudsen, G. M., Maeda, S., Trinidad, J. C., Ioanoviciu, A., Burlingame, A. L., & Mucke, L. (2015) · Nature Neuroscience · doi:10.1038/nn.4067 · Cited by 472 · see citing works
Multiparametric imaging of biological systems by force-distance curve–based AFM
Dufrêne, Y. F., Martínez-Martín, D., Medalsy, I. D., Alsteens, D., & Müller, D. J. (2013) · Nature Methods · doi:10.1038/nmeth.2602 · Cited by 459 · see citing works
Tau phosphorylation: physiological and pathological consequences
Stoothoff, W. H., & Johnson, G. V. W. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.06.017 · Cited by 439 · see citing works
Zur Lehre von der Wirkung der Salze
Hofmeister, F. (1888) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf01838161 · Cited by 439 · see citing works
Post-translational modifications of tau protein in Alzheimer’s disease
Gong, C.-X., Liu, F., Grundke-Iqbal, I., & Iqbal, K. (2005) · Journal of Neural Transmission · doi:10.1007/s00702-004-0221-0 · Cited by 437 · see citing works
Global Hairpin Folding of Tau in Solution
Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H.-J., & Mandelkow, E. (2006) · Biochemistry · doi:10.1021/bi0521543 · Cited by 432 · see citing works
Self-citationTransport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles
Schmidt, H. B., & Görlich, D. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.11.001 · Cited by 413 · see citing works
The Structural Basis of Monoclonal Antibody Alz50's Selectivity for Alzheimer's Disease Pathology
Carmel, G., Mager, E. M., Binder, L. I., & Kuret, J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32789 · Cited by 402 · see citing works
Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase
Hernández-Vega, A., Braun, M., Scharrel, L., Jahnel, M., Wegmann, S., Hyman, B. T., Alberti, S., Diez, S., & Hyman, A. A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.042 · Cited by 395 · see citing works
Self-citationTau aggregation is driven by a transition from random coil to beta sheet structure.
von Bergen, M., Barghorn, S., Biernat, J., Mandelkow, E., & Mandelkow, E. (2005) · Biochimica et Biophysica Acta · doi:10.1016/j.bbadis.2004.09.010 · Cited by 376 · see citing works
Self-citationTakeda, S., Wegmann, S., Cho, H., DeVos, S. L., Commins, C., Roe, A. D., Nicholls, S. B., Carlson, G. A., Pitstick, R., Nobuhara, C. K., et al. (2015) · Nature Communications · doi:10.1038/ncomms9490 · Cited by 371 · see citing works
Self-citationInteraction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity
Vanderweyde, T. E., Apicco, D. J., Youmans-Kidder, K., Ash, P. E. A., Cook, C. N., da Rocha, E. L., Jansen‐West, K. R., Frame, A. A., Citro, A., Leszyk, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.045 · Cited by 346 · see citing works
Phase Separation: Linking Cellular Compartmentalization to Disease
Aguzzi, A., & Altmeyer, M. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.03.004 · Cited by 333 · see citing works
Salminen, A., Kauppinen, A., Suuronen, T., Kaarniranta, K., & Ojala, J. O. (2009) · Journal of Neuroinflammation · doi:10.1186/1742-2094-6-41 · Cited by 327 · see citing works
Naini, S. M. A., & Soussi‐Yanicostas, N. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/151979 · Cited by 318 · see citing works
Droplets Formation and Merging in Two-Phase Flow Microfluidics
Gu, H., Duits, M. H. G., & Mugele, F. G. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12042572 · Cited by 313 · see citing works
RNA stores tau reversibly in complex coacervates
Zhang, X., Lin, Y., Eschmann, N. A., Zhou, H., Rauch, J. N., Hernández, I., Guzman, E., Kosik, K. S., & Han, S. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2002183 · Cited by 308 · see citing works
Goode, B. L., Denis, P. E., Panda, D., Radeke, M. J., Miller, H. P., Wilson, L., & Feinstein, S. C. (1997) · Molecular Biology of the Cell · doi:10.1091/mbc.8.2.353 · Cited by 296 · see citing works
Phase Transitions of Spindle-Associated Protein Regulate Spindle Apparatus Assembly
Jiang, H., Wang, S., Huang, Y., He, X.-N., Cui, H., Zhu, X.-L., & Zheng, Y.-X. (2015) · Cell · doi:10.1016/j.cell.2015.08.010 · Cited by 291 · see citing works
Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins
Ciryam, P., Tartaglia, G. G., Morimoto, R. I., Dobson, C. M., & Vendruscolo, M. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.09.043 · Cited by 270 · see citing works
Saben, J. L., Boudoures, A. L., Shyr, Z. A., Thompson, A. S., Drury, A. M., Zhang, W., Chi, M. M.-Y., Cusumano, A., Scheaffer, S. M., & Moley, K. H. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.065 · Cited by 266 · see citing works
Hiller, G., & Weber, K. K. (1978) · Cell · doi:10.1016/0092-8674(78)90335-5 · Cited by 261 · see citing works
Assemblages: Functional units formed by cellular phase separation
Toretsky, J. A., & Wright, P. E. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201404124 · Cited by 244 · see citing works
Mechanisms of Protein Seeding in Neurodegenerative Diseases
Walker, L. C., Diamond, M. I., Duff, K. E., & Hyman, B. T. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.1453 · Cited by 226 · see citing works
Self-citationReynolds, C. H., Garwood, C. J., Wray, S., Price, C., Kellie, S., Perera, T. P. S., Zvelebil, M., Yang, A., Sheppard, P. W., Varndell, I. M., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709715200 · Cited by 226 · see citing works
Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration
Li, X., Kumar, Y., Zempel, H., Mandelkow, E., Biernat, J., & Mandelkow, E. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.376 · Cited by 222 · see citing works
Self-citationMARKK, a Ste20‐like kinase, activates the polarity‐inducing kinase MARK/PAR‐1
Timm, T., Li, X., Biernat, J., Jiao, J., Mandelkow, E., Vandekerckhove, J., & Mandelkow, E. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg447 · Cited by 198 · see citing works
Self-citationThe fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush
Wegmann, S., Medalsy, I. D., Mandelkow�, E., & Müller, D. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212100110 · Cited by 196 · see citing works
Self-citationThe “Jaws” of the Tau-Microtubule Interaction
Mukrasch, M. D., von Bergen�, M., Biernat, J., Fischer, D., Griesinger, C., Mandelkow�, E., & Zweckstetter, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607159200 · Cited by 196 · see citing works
Self-citationBarghorn, S., Biernat, J., & Mandelkow�, E. (2005) · Humana Press eBooks · doi:10.1385/1-59259-874-9:035 · Cited by 193 · see citing works
Self-citationAlzheimer‐related neuronal protein A68: Specificity and distribution
Wolozin, B. L., & Davies, P. (1987) · Annals of Neurology · doi:10.1002/ana.410220412 · Cited by 178 · see citing works
In Vivo Formation of Vacuolated Multi-phase Compartments Lacking Membranes
Schmidt, H. B., & Rohatgi, R. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.088 · Cited by 178 · see citing works
Li, C., & Götz, J. (2017) · The EMBO Journal · doi:10.15252/embj.201797724 · Cited by 178 · see citing works
Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases
Ciryam, P., Kundra, R., Morimoto, R. I., Dobson, C. M., & Vendruscolo, M. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.12.004 · Cited by 173 · see citing works
Eckermann, K., Mocanu, M.-M., Khlistunova, I., Biernat, J., Nissen, A., Hofmann, A., Schönig, K., Bujard, H., Haemisch, A., Mandelkow, E., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705282200 · Cited by 168 · see citing works
Self-citationOligomer Formation of Tau Protein Hyperphosphorylated in Cells
Tepper, K., Biernat, J., Kumar, S., Wegmann, S., Timm, T., Hübschmann, S., Redecke, L., Mandelkow, E., Müller, D. J., & Mandelkow�, E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.611368 · Cited by 154 · see citing works
Self-citationCleavage and conformational changes of tau protein follow phosphorylation during Alzheimer’s disease
Mondragón‐Rodríguez, S., Basurto‐Islas, G., Santa‐María, I., Mena, R., Binder, L. I., Ávila, J., Smith, M. A., Perry, G. L., & García‐Sierra, F. (2008) · International Journal of Experimental Pathology · doi:10.1111/j.1365-2613.2007.00568.x · Cited by 146 · see citing works
FLEXITau: Quantifying Post-translational Modifications of Tau Protein in Vitro and in Human Disease
Mair, W., Muntel, J., Tepper, K., Tang, S., Biernat, J., Seeley, W. W., Kosik, K. S., Mandelkow�, E., Steen, H., & Steen, J. A. J. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.5b04509 · Cited by 144 · see citing works
Self-citationWang, Y., Garg, S., Mandelkow, E., & Mandelkow�, E. (2010) · Biochemical Society Transactions · doi:10.1042/bst0380955 · Cited by 140 · see citing works
Self-citationAckmann, M., Wiech, H., & Mandelkow�, E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002590200 · Cited by 131 · see citing works
Self-citationRemoval of the projections from cytoplasmic microtubules in vitro by digestion with trypsin.
Vallee, R. B., & Borisy, G. G. (1977) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32839-9 · Cited by 125 · see citing works
The Dissociation of Proteins by Chaotropic Salts
Sawyer, W. H., & Puckridge, J. (1973) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)43151-7 · Cited by 107 · see citing works
Zempel, H., & Mandelkow, E. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0064-1 · Cited by 93 · see citing works
Self-citationZhu, S., Shala, A., Bezginov, A., Sljoka, A., Audette, G. F., & Wilson, D. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120416 · Cited by 88 · see citing works
Kumar, S., Tepper, K., Kaniyappan, S., Biernat, J., Wegmann, S., Mandelkow, E., Müller, D. J., & Mandelkow�, E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.554725 · Cited by 86 · see citing works
Self-citationCell-based Models To Investigate Tau Aggregation
Lim, S., Haque, M. M., Kim, D., Kim, D. J., & Kim, Y. K. (2014) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2014.09.011 · Cited by 84 · see citing works
Zhang, F., Roosen‐Runge, F., Sauter, A., et al. (2012) · Faraday Discussions · doi:10.1039/c2fd20021j · Cited by 84 · see citing works
Structural and Microtubule Binding Properties of Tau Mutants of Frontotemporal Dementias
Fischer, D., Mukrasch, M. D., von Bergen�, M., Kłos-Witkowska, A., Biernat, J., Griesinger, C., Mandelkow�, E., & Zweckstetter, M. (2007) · Biochemistry · doi:10.1021/bi061318s · Cited by 80 · see citing works
Self-citationPhosphorylation of Human Tau Protein by Microtubule Affinity-Regulating Kinase 2
Schwalbe, M., Biernat, J., Bibow, S., Ozenne, V., Jensen, M. R., Kadavath, H., Blackledge, M., Mandelkow, E., & Zweckstetter, M. (2013) · Biochemistry · doi:10.1021/bi401266n · Cited by 78 · see citing works
Self-citationProteolysis of Non-phosphorylated and Phosphorylated Tau by Thrombin
Arai, T., Guo, J., & McGeer, P. L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409234200 · Cited by 75 · see citing works
Guillén‐Boixet, J., Buzón, V., Salvatella, X., et al. (2016) · eLife · doi:10.7554/elife.19298 · Cited by 69 · see citing works
Wildling, L., Rankl, C., Haselgrübler, T., Gruber, H. J., Holy, M., Newman, A. H., Zou, M., Zhu, R., Freissmuth, M., Sitte, H. H., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.304873 · Cited by 68 · see citing works
Pir, G. J., Choudhary, B. C., Mandelkow�, E., & Mandelkow, E. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0096-1 · Cited by 60 · see citing works
Self-citationTau mutations in familial frontotemporal dementia
Spillantini, M. G. (2000) · Brain · doi:10.1093/brain/123.5.857 · Cited by 57 · see citing works
Characteristics of the binding of thioflavin S to tau paired helical filaments
Santa‐María, I., Pérez, M., Hernández, F., Ávila, J., & Moreno, F. J. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9307 · Cited by 53 · see citing works
Phase Separation as a Possible Means of Nuclear Compartmentalization
Aumiller, W. M., Davis, B., & Keating, C. D. (2014) · International review of cytology · doi:10.1016/b978-0-12-800046-5.00005-9 · Cited by 44 · see citing works
Regions of Tau Implicated in the Paired Helical Fragment Core as Defined by NMR
Sillen, A., Leroy, A., Wieruszeski, J., Loyens, A., Beauvillain, J., Buée, L., Landrieu, I., & Lippens, G. M. (2005) · ChemBioChem · doi:10.1002/cbic.200400452 · Cited by 43 · see citing works
Structural studies on the mechanism of protein aggregation in age related neurodegenerative diseases
Eftekharzadeh, B., Hyman, B. T., & Wegmann, S. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.03.001 · Cited by 41 · see citing works
Self-citationA survey of Waterdrop Interaction Experiments
Abbott, C. E. (1977) · Reviews of Geophysics · doi:10.1029/rg015i003p00363 · Cited by 40 · see citing works
Phase Separation of Disordered Protein in the Formation of Membrane-Less Organelles
Nott, T. J., Farber, P. J., Petsalakis, E., et al. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.268 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Liquid-liquid phase separation induces pathogenic tau conformations in vitro
Kanaan, N. M., Hamel, C., Grabinski, T., & Combs, B. (2020) · Nature Communications · doi:10.1038/s41467-020-16580-3 · Cited by 397 · see citing works
Mechanisms of secretion and spreading of pathological tau protein
Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03349-1 · Cited by 304 · see citing works
Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
Abyzov, A., Blackledge, M., & Zweckstetter, M. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00774 · Cited by 215 · see citing works
Hsieh, Y.-C., Guo, C., Yalamanchili, H. K., Abreha, M., Al-Ouran, R., Li, Y., Dammer, E. B., Lah, J. J., Levey, A. I., Bennett, D. A., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.104 · Cited by 196 · see citing works
Acetylation Disfavors Tau Phase Separation
Ferreon, J. C., Jain, A., Choi, K.-J., Tsoi, P. S., MacKenzie, K. R., Jung, S. Y., & Ferreon, A. C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051360 · Cited by 183 · see citing works
RNA binding proteins co-localize with small tau inclusions in tauopathy
Maziuk, B. F., Apicco, D. J., Cruz, A. L., Jiang, L., Ash, P. E. A., da Rocha, E. L., Zhang, C., Yu, W. H., Leszyk, J., Abisambra, J. F., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0574-5 · Cited by 151 · see citing works
Tau filaments in neurodegenerative diseases
Goedert, M. (2018) · FEBS Letters · doi:10.1002/1873-3468.13108 · Cited by 127 · see citing works
Microtubule lattice spacing governs cohesive envelope formation of tau family proteins
Siahaan, V., Tan, R., Humhalova, T., Libusova, L., Lacey, S. E., Tan, T., Dacy, M., Ori-McKenney, K. M., McKenney, R. J., Braun, M., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01096-2 · Cited by 94 · see citing works
Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses
Meng, J. X., Zhang, Y., Saman, D., Haider, A. M., De, S., Sang, J. C., Brown, K., Jiang, K., Humphrey, J., Julian, L., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30461-x · Cited by 84 · see citing works
Bishof, I., Dammer, E. B., Duong, D. M., Kundinger, S. R., Gearing, M., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.001747 · Cited by 80 · see citing works
Ainani, H., Bouchmaa, N., Ben Mrid, R., & El Fatimy, R. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106011 · Cited by 54 · see citing works
Hyman, B. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-023749 · Cited by 39 · see citing works
Self-citationLiquid-liquid phase separation in Alzheimer’s disease
Fu, Q., Zhang, B., Chen, X., & Chu, L. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02407-3 · Cited by 33 · see citing works
Liquid − liquid phase separation of tau: Driving forces, regulation, and biological implications
Li, P., Chen, J., Wang, X., Su, Z., Gao, M., & Huang, Y. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106167 · Cited by 30 · see citing works
Tau liquid–liquid phase separation: At the crossroads of tau physiology and tauopathy
Islam, M., Shen, F., Regmi, D., Petersen, K., Karim, M. R. U., & Du, D. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.30853 · Cited by 28 · see citing works
Li, S., Lu, J., Zeng, K., Lu, X., Zhang, J., Feng, S., Liang, C., Cai, Y., Yao, S., Huang, Q., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71812
- Authors
- Wegmann, S., Eftekharzadeh, B., Tepper, K., Zoltowska, K. M., Bennett, R. E., Dujardin, S., Laskowski, P. R., MacKenzie, D., Kamath, T., Commins, C., Vanderburg, C., Roe, A. D., Fan, Z., Molliex, A. M., Hernandez‐Vega, A., Muller, D., Hyman, A. A., Mandelkow, E., Taylor, J. P., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- German Center for Neurodegenerative Diseases (DE)
- ETH Zurich (CH)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Wegmann, Susanne
- Hyman, Bradley T
- ORCID
- Venue
- The EMBO Journal
- Published
- 2018-02-22
- Volume
- 37
- Issue
- 7
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5881631
- OpenAlex
- W2788827529
- Cited by
- 1,102
- References
- 111
- Citations by year
- 2026: 153 · 2025: 141 · 2024: 156 · 2023: 136 · 2022: 150 · 2021: 137 · 2020: 112 · 2019: 89 · 2018: 26 · 2017: 1
- FWCI
- 62.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Max Planck Digital Library (submittedVersion)
- DZNE Pub (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Funders
- Massachusetts Alzheimer Disease Research Center (P50AG005134)
- Howard Hughes Medical Institute (R35NS097974)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Max‐Planck‐Gesellschaft
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- tau protein, liquid-liquid phase separation, tau aggregation, neurofibrillary tangles, Alzheimer's disease, tauopathy, phosphorylated tau, intrinsically disordered proteins, neurodegenerative diseases
- MeSH terms
- Heterogeneous Nuclear Ribonucleoprotein A1, Aged, 80 and over, Alzheimer Disease, Amino Acid Sequence, Amyotrophic Lateral Sclerosis, Animals, Brain, Cloning, Molecular, DNA-Binding Proteins, Escherichia coli, Female, Humans, Mice, Transgenic, Molecular Weight, Neuroblastoma, Neurons, Phosphorylation, Recombinant Proteins, Neurofibrillary Tangles, tau Proteins, Neurodegenerative Diseases, Sequence Analysis, Protein, Mice, Benzothiazoles, Biophysical Phenomena, HEK293 Cells, Liquid-Liquid Extraction, Sf9 Cells, Protein Aggregation, Pathological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
