Tan R, Lam AJ, Tan T, Han J, Nowakowski DW, Vershinin M, Simó S, Ori-McKenney KM, McKenney RJ. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat Cell Biol. 2019 Sep;21(9):1078-1085. Epub 2019 Sep 2 PubMed.

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  1. Both studies elegantly identify novel interactions between tau and microtubules (MTs) in a physiological setting, either in regulating tau condensation or in protecting MTs from depolymerizing. I have been reminded of a paper from the Safinya lab on the role of tau on MT architecture focusing on the axon initial segment (Chung et al., 2016). This work also focused on the projection domain of tau (see → Fig 3 of Tan et al.). It would be interesting to determine, as a follow-up of McKenney's work, how/whether microtubules gate tau condensation in the axon initial segment, considering that this is the compartment in which action potentials are generated.

    How are these processes affected by pathological tau? In a disease context it has been shown by us that pathological tau impairs action potential generation (neuronal excitability) in a microtubule-dependent manner (Hatch et al., 2017). Considering that the MT caliber differs between axons and dendrites, it might also be worthwhile to assess the role of dendritic tau, again under physiological and pathological conditions. By extension, it would be interesting to find how MAP2 becomes organized in the dendrite, and what the changes are with development.

    References:

    Chung PJ, Song C, Deek J, Miller HP, Li Y, Choi MC, Wilson L, Feinstein SC, Safinya CR. Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment. Nat Commun. 2016 Jul 25;7:12278. PubMed.

    Hatch RJ, Wei Y, Xia D, Götz J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol. 2017 May;133(5):717-730. Epub 2017 Jan 16 PubMed.

    View all comments by Jürgen Götz

  2. Phase states of tau can regulate microtubule function

    These new tau papers advance our knowledge of tau protein function at a mechanistic level. Previous work showed that tau is an RNA-binding protein capable of undergoing liquid-liquid phase separation (LLPS) (Zhang et al., 2017) and contextualized tau with other intrinsically disordered RNA-binding proteins capable of LLPS that can transition to solid inclusions. Subsequently, several other groups extended these data (Wegmann et al., 2018; Hernández-Vega et al., 2017; Ambadipudi  et al., 2017). Underlying all these papers are two questions: (1) Is there a physiological role for tau phase separation? And (2) Is tau LLPS on the pathway to pathological tau aggregation? The heuristic approaches to these two questions often overlap.

    Ackmann et al. (2000) pointed out that tau binding to microtubules is biphasic with a nonsaturable second phase suggestive of tau-tau interactive binding induced by the polyanionic C-terminal domain of tubulin. This would be consistent with the self-assembly of tau in association with other polyanions. Further experiments with Alexa-labeled tau decorated taxol-stabilized microtubules in patches of three to 20 labeled tau molecules that extended up to 1.2 μm (Dixit et al., 2008). More recently clustering of tau has been described in terms of LLPS. When tau droplets were aged in vitro, a thioflavin signal emerged suggesting a conformational change that resembled the fibril of the neurofibrillary tangle (Zhang et al., 2017; Wegmann et al., 2018). This property of tau coacervation was further pinned down to the microtubule-binding repeats, the amyloid-promoting elements of tau (Ambadipudi  et al., 2017); however, other studies including the paper here by Tan et al. indicate a complex relationship of the tau domain structure to tau condensation. However, within tightly packed tau condensates, tau can retain its normal conformation as shown by electron spin resonance (ESR) of tau droplets (Zhang et al., 2017). Tau has also been shown to affect several microtubule regulatory proteins including severing activity (Vale, 1991; Qiang et al., 2006; Yu et al., 2008) and has important effects on microtubule motors (Dixit et al., 2008; Vershinin et al., 2007; Monroy et al., 2018; Seitz et al., 2002). 

    Tan et al. have performed an elegant study that begins with the demonstration that tau initially binds diffusely along the entire microtubule (MT) lattice, but over time expansion of denser regions occurs gated by the nucleotide state of the MT lattice, probably corresponding to the GMP-CPP versus GDP state of the microtubules. This observation allowed the authors to hypothesize that the spacing between tubulin dimers regulates the ability of tau to undergo condensation on the lattice. These condensates passed several tests for LLPS—the ability to FRAP (fluorescence recovery after photobleaching), fuse, and dissolve on addition of 1,6-hexanediol (1,6-HD). From these in vitro studies they transitioned to live cell experiments and reached the conclusion that tau condensates along the microtubule and that its specific interactions with cargo can adjust the velocity and run lengths of retrograde traffic. These studies open a rich territory to find potential effects of pathological tau mutations on condensate formation and on the interactions of condensates with retrograde motors and cargo.  

    The companion paper by Siahaan et al. emphasizes the control of microtubule-severing enzymes by tau, and by implication, microtubule destabilization and axonal degeneration as a result of tau mislocalization. They describe the association of tau with microtubules as cooperatively forming cohesive islands that that are kinetically distinct from tau molecules that individually diffuse on microtubules. Tau islands on microtubules halted the processive movement of kinesin motors and prevented the activity of microtubule-severing enzyme katanin. Tau conferred microtubule protection from severing due to cohesion between the cooperatively binding tau molecules that make up the islands. As expected based on the properties of phase states, which are maintained by weak interactions, small changes in concentration or charge will alter the balance between these two kinetically distinct pools of tau. In fact, the authors showed that the rate of tau unbinding from the islands increased with increasing tau concentration in solution.

    In addition to the important cell biological insights reported in these two papers, they imply the necessity for caution as the field moves toward trials for AD and other tauopathies intended to reduce total tau. Therapeutic strategies that reduce total tau synthesis, such as the use of antisense oligonucleotides, will affect pools of tau on microtubules and consequently microtubule function in ways that are not easily predictable. The implementation of such interventions before we have determined how the dynamical states of tau lead to neurofibrillary tangles is premature.

    References:

    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.

    Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S, Hyman AA. Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase. Cell Rep. 2017 Sep 5;20(10):2304-2312. PubMed.

    Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat Commun. 2017 Aug 17;8(1):275. PubMed.

    Ackmann M, Wiech H, Mandelkow E. Nonsaturable binding indicates clustering of tau on the microtubule surface in a paired helical filament-like conformation. J Biol Chem. 2000 Sep 29;275(39):30335-43. PubMed.

    Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential regulation of dynein and kinesin motor proteins by tau. Science. 2008 Feb 22;319(5866):1086-9. PubMed.

    Vale RD. Severing of stable microtubules by a mitotically activated protein in Xenopus egg extracts. Cell. 1991 Feb 22;64(4):827-39. PubMed.

    Qiang L, Yu W, Andreadis A, Luo M, Baas PW. Tau protects microtubules in the axon from severing by katanin. J Neurosci. 2006 Mar 22;26(12):3120-9. PubMed.

    Yu W, Qiang L, Solowska JM, Karabay A, Korulu S, Baas PW. The microtubule-severing proteins spastin and katanin participate differently in the formation of axonal branches. Mol Biol Cell. 2008 Apr;19(4):1485-98. Epub 2008 Jan 30 PubMed.

    Vershinin M, Carter BC, Razafsky DS, King SJ, Gross SP. Multiple-motor based transport and its regulation by Tau. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):87-92. PubMed.

    Monroy BY, Sawyer DL, Ackermann BE, Borden MM, Tan TC, Ori-McKenney KM. Competition between microtubule-associated proteins directs motor transport. Nat Commun. 2018 Apr 16;9(1):1487. PubMed.

    Seitz A, Kojima H, Oiwa K, Mandelkow EM, Song YH, Mandelkow E. Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J. 2002 Sep 16;21(18):4896-905. PubMed.

    View all comments by Kenneth Kosik

  3. These papers by Siahaan et al. and Tan et al. add to a growing body of work emphasizing the importance of phase separation in biology, and the specific importance of this work in tau biology. Previous work by the Hyman laboratory demonstrated the condensation and phase separation of tau around microtubules (Hernández-Vega et al., 2017). The current work extends our understanding greatly, and in multiple directions.

    The first striking point is that the experiments can use very low, highly relevant physiological levels of tau (20 nM); this might be because the condensation of tau around microtubules allows a ready nidus for concentrating the protein. These results contrast with phase separation of tau alone (with RNA), which requires micromolar amounts.

    Other points are equally interesting. The McKenney group identifies regions critical for tau condensation that differ from that observed with tau alone (projection domain vs. microtubule-binding domain). The group also shows how condensation of tau regulates particular microtubule functions and reveals a fascinating selectivity of tau condensation for curved microtubules. Meanwhile, the manuscript by the Braun/Lansky/Hernandez-Vega group shows domains of tau on microtubules that exhibit differential dynamic movement.

    These studies begin to extend our understanding of the importance of phase separation in biology, and might ultimately impact on our understanding of the pathophysiology of tauopathies.

    References:

    Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S, Hyman AA. Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase. Cell Rep. 2017 Sep 5;20(10):2304-2312. PubMed.

    View all comments by Benjamin Wolozin

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