Interplay between tau and α-synuclein liquid-liquid phase separation

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 alpha-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 alpha-synuclein with tau and its consequences on tau LLPS. We find alpha-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 alpha-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 alpha-synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy-terminal domain of alpha-synuclein with the proline-rich region P2 of tau is required for the recruitment of alpha-synuclein into tau droplets. The combined data suggest that the concentration of alpha-synuclein into tau-associated condensates can contribute to synergistic aSyn/tau pathologies.

Automated summary

In patients with Parkinson's disease and dementia, interactions between tau protein pathology and alpha-synuclein pathology may have synergistic effects, contributing to a worse prognosis. Understanding the mechanisms of this interaction can help clarify the relationship between these two distinct pathologies.