By Ben Kerrigan-
Recent research involving academics at Cambridge University has unveiled a promising avenue in the fight against Alzheimer’s disease by focusing on protein phase separation (PPS) in cellular processes.
This innovative approach could potentially lead to novel interventions aimed at mitigating the pathological processes associated with Alzheimer’s.
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Scientists have long known that protein phase separation plays a crucial role in various biological functions within cells.
However, when PPS occurs at the wrong place or time, it can result in molecular clogs or aggregates linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Additionally, poorly formed cellular condensates due to PPS may contribute to cancer development and could offer insights into the aging process.
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Recognizing the growing connection between human diseases and the PPS process, researchers have been actively seeking ways to identify potential therapeutic targets based on PPS regulation.
In a groundbreaking collaboration, Insilico Medicine, a clinical-stage generative AI-driven drug discovery company, and the University of Cambridge have jointly published a paper in the Proceedings of the National Academy of Sciences (PNAS).
The study employed a combination of Insilico’s proprietary AI-driven target identification engine, PandaOmics, and the FuzDrop method, which predicts protein separation.
PandaOmics integrates multiple omics and text-based AI bioinformatics models to assess the potential of proteins as therapeutic targets.
The FuzDrop, developed by Professor Michele Vendruscolo’s(pictured) group at the University of Cambridge, calculates a protein’s propensity to undergo spontaneous phase separation, aiding in the identification of proteins likely to form liquid-liquid phase-separated condensates.
Professor Michele Vendruscolo, Co-Director of the Centre for Misfolding Diseases at the University of Cambridge and lead author of the paper, emphasized the challenge of understanding the role of protein phase separation in cellular functions and its association with human disease.
He stated, “By working with Insilico Medicine, we have developed a multi-omic approach to systematically address this problem and identify a variety of possible targets for therapeutic intervention. We have thus provided a roadmap for researchers to navigate this complex terrain.”
Using this approach, the researchers conducted a large-scale multi-omic study of human sample data, quantified the relative impact of PPS in regulating various pathological processes linked to human disease, and generated a list of potential therapeutic targets for diseases associated with PPS.
Importantly, the study validated the phase separation behaviors of three predicted Alzheimer’s disease targets (MARCKS, CAMKK2, and p62) in cell models of Alzheimer’s disease.
This experimental validation suggests that modulating the formation and behavior of these condensates could lead to novel interventions to combat Alzheimer’s disease’s pathological processes.
Frank Pun, PhD, Head of Insilico Medicine Hong Kong and co-author of the paper, expressed optimism about the collaboration’s potential impact. He stated, “We anticipate facilitating the translation of this preclinical research into novel therapeutic interventions in the near future.”
This pioneering study offers fresh hope in the quest to understand and ultimately combat Alzheimer’s disease by focusing on protein phase separation and identifying potential therapeutic targets for intervention.
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