Tau liquid-liquid phase separation: At the crossroads of tau physiology and tauopathy

Abstract

Abnormal deposition of tau in neurons is a hallmark of Alzheimer's disease and several other neurodegenerative disorders. In the past decades, extensive efforts have been made to explore the mechanistic pathways underlying the development of tauopathies. Recently, the discovery of tau droplet formation by liquid-liquid phase separation (LLPS) has received a great deal of attention. It has been reported that tau condensates have a biological role in promoting and stabilizing microtubule (MT) assembly. Furthermore, it has been hypothesized that the transition of phase-separated tau droplets to a gel-like state and then to fibrils is associated with the pathology of neurodegenerative diseases. In this review, we outline LLPS, the structural disorder that facilitates tau droplet formation, the effects of posttranslational modification of tau on condensate formation, the physiological function of tau droplets, the pathways from droplet to toxic fibrils, and the therapeutic strategies for tauopathies that might evolve from toxic droplets. We expect a deeper understanding of tau LLPS will provide additional insights into tau physiology and tauopathies.

Keywords: condensate; microtubule; phase separation; tau; tauopathy.

Fig. 1.

Schematic representation of tau isoforms found in the human brain. N1-N2 are N-terminal inserts; P1-P2 are the fragments in the middle proline-rich region; R1-R4 are four repeat domains at the C-terminal end. N2 is absent in 1N4R; both N1 and N2 are missing in 0N4R; R2 is lacking in 2N3R; N2 and R2 are absent in 1N3R; N1, N2, and R2 are missing in 0N3R.

Fig. 2.

Physicochemical properties of tau. (a) Full-length primary sequence of tau (2N4R). (b) Prediction of IDRs in tau sequence using the IUPred3A algorithm [77]. Residues in the highlighted region (above 0.5) of the graph are predicted to be disordered, with higher values corresponding to a higher probability of disorder. (c) Hopp-Woods hydrophilicity scale was attained by taking the moving average of the five amino acid hydrophilicity values along the polypeptide chain on the ExPASy server [74]. Values higher than zero are considered hydrophilic, with higher values corresponding to higher hydrophilicity. (d) Distribution of polarized charge along the primary sequence (obtained using EMBOSS bioinformatics, [76]).

Fig. 3.

Schematic representation of LLPS of tau under the influence of various forces. Tau phase separation may undergo through self-coacervation (top flow), through the interaction with other molecules such as polyanions (middle flow), or in a combination of both (bottom flow).

Fig. 4.

Schematic illustration of tau condensate promoting microtubule (MT) assembly. Self-coacervated tau droplets can promote MT assembly through the partitioning of tubulin monomers (top flow); complex-coacervated (for example, with RNA) tau can promote MT assembly through competitive partitioning of tubulin monomers into the condensates (bottom flow) [82]. Self-coacervated droplets produce thin-curvy MT, whereas complex-coacervated droplets produce thick MT [82].

Fig. 5.

Schematic representation of tau condensate and fibrils in a neuron. After being formed in the physiological environment (a), tau droplets can perform physiological functions such as MT stabilization [82,104]. Tau droplets can be found (b) in the cytosol, around the outer nuclear envelope, or in the nucleus [30,82]. Tau fibrils (c), a major pathological hallmark of tauopathies, are postulated to be generated from condensates, though in vivo evidence is yet to be observed. Fibrils in the cell can be seen in the cytosol or adjacent to the outer nuclear envelope [14,30,82].