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.

Atomic force microscopy of spherical intermediates on the pathway to fibril formation of influenza A virus nuclear export protein

“…One of the pathways, involving the MLPs as intermediates, includes the following stages (Figure 5): Numerous attempts have been done previously to establish links between various aggregates in protein mixtures (Ecroyd et al, 2008;Lindgren et al, 2005;Ruggeri et al, 2015). In part, similar mechanisms, displayed in the scheme (Figure 5), were previously described (with variations) for self-assembly of other proteins (Ecroyd et al, 2008;Hardenberg et al, 2021;Islam et al, 2022;Lindgren et al, 2005;Peskett et al, 2018;Ruggeri et al, 2015) (see also for review Almeida & Brito, 2020;Vendruscolo & Fuxreiter, 2022;Wei et al, 2017). In particular, the mechanism of amyloid formation through "supramolecular globular" intermediates was first proposed for PrP and A-beta in the study by Moore et al (Moore et al, 2007).…”

Liquid-Liquid Phase Separation Promotes Protein Aggregation and Its Implications in Ferroptosis in Parkinson’s Disease Dementia

“…Due to the interaction between heterotypic proteins and RNA at the molecular level, when enough biological macromolecules are accumulated in the cell in proportion, the condensate will be formed [26][27][28]. Although the self-assembly of these proteins follows strict procedures in normal cells, it is unclear how these membraneless organelles maintain their metastable liquid or gel phase to prevent solid aggregation, thereby preventing abnormal phase transformation leading to pathological amyloid aggregation causing neurodegenerative diseases such as PDD [29].…”

Effects of Charged Polyelectrolytes on Amyloid Fibril Formation of a Tau Fragment

“…7 The residual sequence of 2N4R (Figure 1) can be divided into several regions, where the N-terminus (with two inserts, N1 and N2) is followed by the proline-rich region (P1 and P2), the microtubule binding region composed of four pseudo-repeats (R1−R4), and a shorter C-terminal tail. 6,8,9 Tau is a highly soluble protein with a small number of hydrophobic residues in the sequence, and the molecule has a tendency to fluctuate among different conformations without having a specific stable tertiary structure, which makes tau an intrinsically disordered protein (IDP). 6,8,9 In order to aggregate into fibrils, tau usually requires additional external factors or post-translational modifications that convert it to a pro-aggregant.…”

“…6,8,9 Tau is a highly soluble protein with a small number of hydrophobic residues in the sequence, and the molecule has a tendency to fluctuate among different conformations without having a specific stable tertiary structure, which makes tau an intrinsically disordered protein (IDP). 6,8,9 In order to aggregate into fibrils, tau usually requires additional external factors or post-translational modifications that convert it to a pro-aggregant. 10−12 Charged anionic cofactors, such as sulfated glycosaminoglycans, nucleic acids, and fatty acids, have been found to induce aggregation of tau, presumably by assisting in overcoming the nucleation barrier on the aggregation pathway.…”

“…Among six different tau isoforms expressed in humans, the longest one (2N4R) contains 441 residues . The residual sequence of 2N4R (Figure ) can be divided into several regions, where the N-terminus (with two inserts, N1 and N2) is followed by the proline-rich region (P1 and P2), the microtubule binding region composed of four pseudo-repeats (R1–R4), and a shorter C-terminal tail. ,, Tau is a highly soluble protein with a small number of hydrophobic residues in the sequence, and the molecule has a tendency to fluctuate among different conformations without having a specific stable tertiary structure, which makes tau an intrinsically disordered protein (IDP). ,, In order to aggregate into fibrils, tau usually requires additional external factors or post-translational modifications that convert it to a pro-aggregant. − Charged anionic cofactors, such as sulfated glycosaminoglycans, nucleic acids, and fatty acids, have been found to induce aggregation of tau, presumably by assisting in overcoming the nucleation barrier on the aggregation pathway. − For example, the colocalization of NFTs and heparan sulfate, a highly acidic glycosaminoglycan (GAG) modified by sulfate, in the isolated brain samples of AD patients suggests an important role of this polyanionic cofactor in tau fibrillation in vivo . It is suggested that the polyanionic molecule can interact electrostatically with positively charged residues in the repeat regions of tau, thereby reducing electrostatic repulsions of the repeat regions, alleviating tau–tau interaction, and stabilizing the β-conformation. ,, Given the importance of electrostatic interactions in the interactions of anionic polymers and tau, as well as polyanion-mediated self-association and aggregation of tau, one would hypothesize that polyelectrolytes containing positive charges may play an opposite role and interfere with tau aggregation, although few such studies have been reported so far.…”