Tau:Prion Multiphasic Condensate Reminiscent of Dysregulated Coacervation in Neuropathology

Living cells are brimming with active biomolecules such as proteins, nucleic acids, and small regulatory molecules in a dense fluidic environment, which must be organized in a spatiotemporal manner to achieve functional coherence. Apart from traditionally studied membrane-bound organelles, research over the past years has now revealed that cells can also achieve compartmentalization by forming non-canonical membrane-less assemblies via phase separation, similar to what we observe in our daily lives, such as oil separating from a vinaigrette. 

Such membrane-less organelles, including Nucleoli, P-bodies, and Cajal bodies are usually multicomponent entities that are involved in various physiological processes such as gene regulation, and stress response. They facilitate the reversible, rapid assembly and disassembly of a large number of biomolecules in response to changing environmental conditions or cellular signals. However, these processes can also contribute to the development of diseases. For instance, abnormal coacervation of proteins can lead to the formation of protein aggregates, which are commonly associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The dysregulation of complex coacervation has also been implicated in other disorders such as cancer and metabolic abnormalities.

Therefore, understanding the mechanisms that underlie complex coacervation and multiphasic condensation is important for discerning the pathophysiology of such diseases related to protein aggregation and abnormal coacervation. Researchers are studying these processes to identify potential targets for drug development and to improve our understanding of disease progression.

Our findings indicate that tau and prion proteins, which are found in neurons, can interact electrostatically in a domain-specific manner to form liquid-like condensates. These condensates show characteristics of liquid droplets, namely, fusion, dripping, and wetting. Further, these tau:prion droplets can be tuned by RNA, resulting in immiscible multiphasic condensates, reminiscent of nucleolar condensates, of different morphologies ranging from core-shell to nested droplets to inverted core-shell. Additionally, our research shows that these liquid-like condensates can transform over time into solid-like amyloid species similar to pathological aggregates seen in certain neurodegenerative diseases.