Interplay between tau and α‐synuclein liquid–liquid phase separation

Abstract

In Parkinson's disease with dementia, up to 50% of patients develop a high number of tau‐containing neurofibrillary tangles. Tau‐based pathologies may thus act synergistically with the α‐synuclein pathology to confer a worse prognosis. A better understanding of the relationship between the two distinct pathologies is therefore required. Liquid–liquid phase separation (LLPS) of proteins has recently been shown to be important for protein aggregation involved in amyotrophic lateral sclerosis, whereas tau phase separation has been linked to Alzheimer's disease. We therefore investigated the interaction of α‐synuclein with tau and its consequences on tau LLPS. We find α‐synuclein to have a low propensity for both, self‐coacervation and RNA‐mediated LLPS at pH 7.4. However, full‐length but not carboxy‐terminally truncated α‐synuclein efficiently partitions into tau/RNA droplets. We further demonstrate that Cdk2‐phosphorylation promotes the concentration of tau into RNA‐induced droplets, but at the same time decreases the amount of α‐synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy‐terminal domain of α‐synuclein with the proline‐rich region P2 of tau is required for the recruitment of α‐synuclein into tau droplets. The combined data suggest that the concentration of α‐synuclein into tau‐associated condensates can contribute to synergistic aSyn/tau pathologies.

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

“…For example, in Parkinson's disease with dementia, patients have not only insoluble deposits of α‐synuclein, but up to 50% of patients also develop tau‐containing neurofibrillary tangles 167 . While α‐synuclein itself has a low propensity for self‐coacervation in physiological conditions, it readily concentrates in a phosphorylation‐dependent manner in tau droplets 168 (Figure 3). In addition, α‐synuclein fibrils associate with tau droplets 168 .…”

“…While α‐synuclein itself has a low propensity for self‐coacervation in physiological conditions, it readily concentrates in a phosphorylation‐dependent manner in tau droplets 168 (Figure 3). In addition, α‐synuclein fibrils associate with tau droplets 168 . Because high concentrations of both tau and α‐synuclein are reached in the droplets, their aggregation is promoted.…”

Spatiotemporal Modulations in Heterotypic Condensates of Prion and α-Synuclein Control Phase Transitions and Amyloid Conversion

“…However, α-Syn did not undergo phase separation upon the addition of RNA, as reported previously. 31 We next studied the behavior of preformed PrP-α-Syn complex coacervates in the presence of RNA. Turbidity measurements complemented with microscopic observations revealed a reentrant phase transition of these heterotypic condensates in the presence of RNA under our experimental conditions (Fig.…”

“…4 Therefore, aberrant phase transitions of these protein-rich droplets can also promote deleterious fibrillization that is associated with various neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and so forth. 31–36…”

Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties

“…We have here shown how our model may be used to help elucidate the residues that are important for LLPS of IDPs with UCST behaviour. Further, we suggest the model could be applied to study the influence of disease-associated mutations on the material properties of protein self-coacervates (79,80), the LLPS of protein mixtures as a function of composition, and the partitioning of proteins that do not readily undergo phase separation alone into condensates formed by other proteins (81,82). Finally, owing to the generalized parameter-learning approach, the model could readily be refined as new experimental data are collected and it should be possible to extend it to account for specific pairwise interactions such as cation-π interactions (25), PTMs (83), the salting-out effect (84) and the temperature dependence of solvent mediated interactions (70).…”