The chemistry and physics of RNP granules: how they form, age and cause disease

Recent studies suggest that defective ribonucleoprotein (RNP) granules and altered RNA processing cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, defective RNP granules only develop late in life, suggesting that young cells have mechanisms in place to prevent their formation. We recently demonstrated that physiological RNP granules form through phase separation in the cytoplasm and adopt a liquid-like state, but with time transition into an aberrant disease-associated state with solid material properties. Focussing on this conceptual advance, we will 1) investigate the molecular mechanisms of RNP granule formation; 2) pinpoint the molecular events that lead to aberrant RNPs, focusing on disease-associated mutations, changes in environmental conditions, post-translational modifications and molecules with fluidizing or solidifying effects; and 3) define the mechanisms of RNP quality control, which prevent aberrant phase transitions or reverse RNP aggregates to their normal state, thus rescuing a cell from an otherwise fatal condition. Key to the project are recently developed methodologies to reconstitute RNPs from purified proteins and RNAs, and biophysical techniques to analyse the material properties of RNP granules. Combined with our ability to perform time-resolved studies of RNPs in living cells and our thematic focus on the link between RNP dynamics and functionality, this project represents a systematic and realistic approach to tackling the essential question of how RNP granules form and why they cause disease. We expect that our findings will have impact far beyond ALS and FTD, because aberrant phase transitions may be at the heart of many protein-misfolding diseases. We envision that our findings will lead to new therapeutic interventions that may significantly improve the prospects of patients afflicted with these diseases.