Tau Condensation Research Articles

Cellular polyamines condense hyperphosphorylated Tau, triggering Alzheimer\u2019s disease

Many gaps in our understanding of Alzheimer’s disease remain despite intense research efforts. One such prominent gap is the mechanism of Tau condensation and fibrillization. One viewpoint is that positively charged Tau is condensed by cytosolic polyanions. However, this hypothesis is likely based on an overestimation of the abundance and stability of cytosolic polyanions and an underestimation of crucial intracellular constituents – the cationic polyamines. Here, we propose an alternative mechanism grounded in cellular biology. We describe extensive molecular dynamics simulations and analysis on physiologically relevant model systems, which suggest that it is not positively charged, unmodified Tau that is condensed by cytosolic polyanions but negatively charged, hyperphosphorylated Tau that is condensed by cytosolic polycations. Our work has broad implications for anti-Alzheimer’s research and drug development and the broader field of tauopathies in general, potentially paving the way to future etiologic therapies.

Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Microtubules gate tau condensation to spatially regulate microtubule functions.

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer’s disease and other dementias1, yet the physiological state of tau molecules within cells remains unclear. Using single molecule imaging, we directly observe that the microtubule lattice regulates reversible tau self-association, leading to localized, dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of microtubule severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible self-association of tau molecules, gated by the microtubule lattice, is an important mechanism of tau’s biological functions, and that oligomerization of tau is a common property shared between the physiological and disease forms of the molecule.

Liquid-Liquid Phase Separation of Tau Protein in Neurobiology and Pathology.

Tau is an intrinsically unfolded protein that, aside from its important role in the regulation of microtubule stability, harbors an emerging number of other functions. In order to find explanations for some longtime unsolved aspects of neuronal tau biology in the brain, we may have to step aside from observing tau molecules in dilute solutions, and from assuming a mono-molecular physicochemical behavior of molecules in the cell. Liquid condensed phases of tau proteins, which form through the biophysical process of liquid-liquid phase separation (LLPS), behave like liquids and thereby offer a new regime of interactions in the cell. So far, there is evidence that tau condensates (i) play a role for neurodegenerative diseases by transitioning into aggregated forms of tau, (ii) are involved in microtubule binding, nucleation, and bundling, and (iii) are interacting with RNA molecules, which could impact RNA homeostasis and transcription. Likewise the functions of monomeric tau, also tau condensation is regulated by post-translational modifications and can be influenced by the local environment, for example in neuronal sub-compartments. However, we are just beginning to understand the physicochemistry of tau LLPS, and the biological role of tau condensation has to be explored in the next years.

Top mode standard model in six dimensions

We construct a top-mode standard model where the third generation fermions and the SU(2)_L \times U(1)_Y gauge bosons are put on a 6-dimensional brane(5-brane) with the extra dimensions compactified on the TeV scale(R_5^{-1}=R_6^{-1} \equiv R^{-1}= 1-10 TeV), while only the gluons live in a compactified 8-dimensional bulk(R_7^{-1}=R_8^{-1} \equiv \Lambda \gg R^{-1}).On the 5-brane, Kaluza-Klein (KK) modes of the bulk gluons give rise to induced four-fermion interactions which, combined with the gauge interactions, are shown to be strong enough to trigger the top quark condensate, based on the dynamics of 6-dimensional gauged Nambu-Jona-Lasinio (NJL) model. Moreover, we can use a freedom of the brane positions to tune the four-fermion coupling close to the critical line of 6-dimensional gauged NJL model, so that the gap equation can ensure the top condensate on the weak scale while keeping other fermions massless. There actually exists a scale (``tMAC scale''), \Lambda_{\rm tM} = (7.8-11.0) R^{-1}, where the running gauge couplings combined with the induced four-fermion interactions trigger only the top condensate while no bottom and tau condensates. Furthermore, presence of such explicit four-fermion interactions enables us to formulate straightforwardly the compositeness conditions at \Lambda=\Lambda_{\rm tM}, which, through the renormalization-group analysis, yields a prediction of masses of the top quark and the Higgs boson, m_t = 177 - 187 GeV and m_H = 183 - 207 GeV.

Most attractive channel analysis in the top mode standard model with extra dimensions

We perform the most attractive channel (MAC) analysis in the top mode standard model with TeV-scale extra dimensions, where the standard model gauge bosons and the third generation of quarks and leptons are put in D(=6,8,10,...) dimensions. In such a model, bulk gauge couplings rapidly grow in the ultraviolet region. In order to make the scenario viable, only the attractive force of the top condensate should exceed the critical coupling, while other channels such as the bottom and tau condensates should not. We then find that the top condensate can be the MAC for D=8, whereas the tau condensation is favored for D=6. The analysis for D=10 strongly depends on the regularization scheme. We predict masses of the top (m_t) and the Higgs (m_H), m_t=172-175 GeV and m_H=176-188 GeV for D=8, based on the renormalization group for the top Yukawa and Higgs quartic couplings with the compositeness conditions at the scale where the bulk top condenses. The Higgs boson in such a characteristic mass range will be immediately discovered in H -> WW^(*)/ZZ^(*) once the LHC starts.