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Tau Prion Condensate Mimics Dysregulated Coacervation in Neuropathology

Work done in the lab of Prof. Samrat Mukhopadhyay’s Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Mohali, 

About author

Sandeep K. Rai

Born in the Deoria district of Uttar Pradesh, Sandeep K. Rai completed his graduation (B.Sc.) from the Madan Mohan Malviya P.G. College, Bhatpar Rani, Deoria (U.P.). After graduation, he joined IIT Delhi to pursue a Master’s degree in Chemistry (2016-18). In 2018, Sandeep joined the Department of Chemical Sciences at IISER Mohali to pursue his Ph.D. under the supervision of Professor Samrat Mukhopadhyay. In the Mukhopadhyay Lab, he is studying the complex coacervates of Intrinsically Disordered Proteins using state-of-the-art techniques such as AFM, steady-state, time-resolved, single-molecule fluorescence spectroscopy, and super-resolution microscopy. Outside his scientific pursuits, he likes to sleep and watch documentaries.

Interview

How would you explain your research outcomes to the non-scientific community?

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.

Tau and prion proteins undergo heterotypic phase separation fueled by electrostatic interactions. These complex coacervates of tau:PrP matured into fibrils over time. Moreover, in the presence of RNA, these condensates adopted varying kinds of multiphasic morphologies.
Tau and prion proteins undergo heterotypic phase separation fueled by electrostatic interactions. These complex coacervates of tau:PrP matured into fibrils over time. Moreover, in the presence of RNA, these condensates adopted varying kinds of multiphasic morphologies.

How do these findings contribute to your research area?

Our results offer mechanistic insights into the multicomponent macromolecular phase separation connected to physiology and overlapping neuropathological characteristics. Reports have indicated the accumulation of neurofibrillary tangles of tau in the brains of patients affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA). Additionally, Gerstmann-Sträussler-Scheinker (GSS) syndrome is also attributed partly to tau-prion deposits. Taken together, our findings indicate that the prion protein is likely to play a central role in the etiology of many overlapping neurodegenerative diseases. Our work further strengthens the common mechanism for the development and progression of late-life neurodegenerative diseases and highlights the importance of focusing on the cellular prion protein as an impactful therapeutic target compared to many other proteinaceous inclusions.

“Our findings indicate that the prion protein is likely to play a central role in the etiology of many overlapping neurodegenerative diseases. “

What was the exciting moment during your research?

The entire journey for this project was full of excitement. From forming tau and Prion droplets to seeing beautiful rod-like fibrils under the super-resolution microscope. But if I must choose one, then, it was when we saw immiscible multiphasic condensates of different architecture, from core-shell to nested droplets, in the presence of RNA under the microscope. Moreover, when we added RNase into the mixture, we could tune the multiphasic to the biphasic transition of tau-prion droplets.

What do you hope to do next?

In the Mukhopadhyay Lab, I have been studying the biophysical aspects of complex coacervates in vitro using tools such as Atomic Force Microscopy (AFM), steady state- and time-resolved fluorescence spectroscopy, and super-resolution microscopy. In the coming future, I will be asking more detailed questions related to the mechanistic underpinnings governing the physical properties of these coacervates at a single-molecule level using our sm-FRET (Single-molecule Förster resonance energy transfer) setup.

Furthermore, I would like to explore the biological aspects of phase separation including its essential role in transcriptional regulation and cellular signaling. Venturing into gene editing coupled with an in situ approach, which finds direct implications in drug development, is what I plan to do in the future.

Where do you seek scientific inspiration from?

My primary scientific inspiration comes from my surroundings, my PI, the members of the Mukhopadhyay Lab, and my peers. Being associated with a group of talented, hardworking, and curious people who have the courage and motivation to go all-out toward asking and answering significant questions in their respective fields acts as fuel for my journey. Last but not the least, the happiness of learning something new and discovering significant results that nobody in the world knows except you, even if it may be for an infinitesimally small moment, is my biggest motivation.

How do you intend to help Indian science improve?

Considering the scarcity of resources compared to the western part of the globe, Indian research has advanced dramatically in recent years. I feel that science can only advance if there is a mutual exchange of knowledge and expertise between its different domains. We need interdisciplinary programs and goals to match up with the west. Moreover, we also need to continue supporting basic sciences. After completing my postdoctoral training abroad, I would like to join Indian academia. I also strive to improve the research environment by undertaking more collaborative research, developing communication between different fields of interest, and encouraging life scientists to ask more fundamental questions.

Reference

Rai, S. K.; Khanna, R.; Avni, A.; Mukhopadhyay, S., Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates. Proceedings of the National Academy of Sciences 2023, 120 (2), e2216338120.

https://doi.org/10.1073/pnas.2216338120

Copy Editor: Nivedita Kamath

For interview related queries, write to us at interview.biopatrika@gmail.com

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