Objective 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 will1) 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. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineneurologydementiamedical and health sciencesbasic medicinephysiologynatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis Keywords RNP granules RNA metabolism Phase transition Protein aggregation Proteostasis Aging Neurodegenerative disease ALS Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2016-COG - ERC Consolidator Grant Call for proposal ERC-2016-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Coordinator TECHNISCHE UNIVERSITAET DRESDEN Net EU contribution € 1 284 801,06 Address Helmholtzstrasse 10 01069 Dresden Germany See on map Region Sachsen Dresden Dresden, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all TECHNISCHE UNIVERSITAET DRESDEN Germany Net EU contribution € 1 284 801,06 Address Helmholtzstrasse 10 01069 Dresden See on map Region Sachsen Dresden Dresden, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Participation ended Germany Net EU contribution € 646 501,94 Address Hofgartenstrasse 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
