The ERC project LLPS-NMR aimed to tackle a fundamental challenge in modern biology and chemistry: understanding the molecular mechanisms of liquid-liquid phase separation (LLPS) in biomolecules. LLPS is a thermodynamic phenomenon where molecules demix into condensed liquid-like phases, forming biomolecular condensates. These condensates play crucial roles in cellular organization, compartmentalization, and regulation of biochemical reactions, but their misregulation is implicated in diseases like Alzheimer's disease (AD), Parkinson’s disease (PD), and ALS. Despite their importance, LLPS processes were largely studied using low-resolution methods like light microscopy, leaving critical questions unanswered about the structure, dynamics, and regulation of proteins in these states.
Understanding LLPS is critical for:
-Disease Mechanisms: Misregulation of LLPS is linked to pathological aggregation in neurodegenerative diseases such as AD and PD. Insights into LLPS could lead to new diagnostic tools and treatments.
-Therapeutics: By uncovering how phase-separated states form and function, the project provides a foundation for designing therapeutic interventions targeting LLPS-related processes.
-Fundamental Biology: LLPS plays a role in essential cellular functions like gene expression, RNA metabolism, and stress responses. Gaining high-resolution insights transforms our understanding of how cells are spatially and temporally organized.
The overall objectives of the LLPS-NMR project were to:
-Develop novel NMR spectroscopy techniques to overcome the resolution barrier, advancing from micrometer to sub-nanometer scales for the study of phase-separated biomolecules.
-Elucidate the molecular structure and dynamics of intrinsically disordered proteins (IDPs) in liquid-like condensates.
-Disentangle the chemical reactions and interactions occurring within phase-separated compartments.
-Understand the regulatory mechanisms of LLPS, focusing on how post-translational modifications, nucleic acids, and other cellular factors influence phase behavior.
-Identify pathological mechanisms of LLPS dysregulation in diseases like Alzheimer’s disease.
