Project description
Exploring the mechanism of protein aggregation in neurodegenerative disorders
Cells carry out most biochemical processes in membrane-bound or membraneless organelles. Recent evidence suggests that liquid–liquid phase separation (LLPS) is the key mechanism that drives proteins into forming membraneless organelles. The EU-funded InMIND project is interested to understand how LLPS is implicated in neurodegenerative disorders, where intrinsically disordered proteins form insoluble aggregates and cause neuronal dysfunction and death. The project will unveil the molecular determinants of LLPS and screen small-molecule compounds that prohibit the formation of biomolecular condensates, opening avenues for innovative therapeutic strategies in neurodegenerative disorders.
Objective
With population ageing and the lack of effective treatments, neurodegenerative diseases (NDs) are expected to pose an increasingly severe challenge to healthcare systems worldwide. A hallmark of NDs is the presence of insoluble aggregates of intrinsically disordered proteins (IDPs) and proteins with disordered regions in neuronal cells. Growing evidence suggests that these disease-associated proteins condense into liquid-like droplets through liquid-liquid phase separation (LLPS). Dysregulation of this process results in the maturation of the liquid-like droplet into a dynamically arrested state, promoting the formation of putatively neurotoxic oligomers and amyloid fibrils.
In this project, I will first develop a molecular model that accurately predicts LLPS of IDPs from amino acid sequence and solution conditions. Second, through large-scale simulations of IDPs, I will elucidate the influence of mutations and post-translational modifications on the material properties of protein condensates. Third, I will employ the model to identify small molecules that preferentially partition into the protein-dense phase and enhance the dynamics of the protein network of the condensate. My findings will shed light on the molecular determinants of LLPS and contribute to explore an innovative therapeutic strategy for NDs, wherein small-molecule compounds prevent aberrant liquid-to-hydrogel-like transitions of biomolecular condensates. The project will enable me to apply my expertise in physical chemistry to therapeutically-relevant biological systems, acquire new competencies in chemoinformatics and project management, and establish myself as a high-quality researcher in the field of biomolecular condensates. The group of Prof. Kresten Lindorff-Larsen in the SBiN-Lab section at the University of Copenhagen will provide an excellent environment with world-leading experts in integrative structural biology and biophysics.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
1165 Kobenhavn
Denmark