Objectif Formation of amyloid-like protein aggregates is the hallmark of a number of neurodegenerative diseases, but how the aggregation process is linked with cytotoxicity and cell death remains unclear. The goal of this pro¬ject is to elucidate the basic mechanisms of aggregate toxicity and how it affects the biological system in its entirety. We will analyse cell culture and mouse models of Huntington’s disease, amyotrophic lateral sclero¬sis and Alzheimer’s disease using a trans-disciplinary approach combining cellular biochemistry, quantita¬tive proteomics and 3D cryo-electron tomography. The effects of aggregating protein species (APS) formed by designer proteins and authentic disease proteins will be compared to define general and disease-specific toxicity mechanisms. The main aims of this project are:1. To determine the sequence of cellular events occurring during toxic protein aggregation. Live cell imaging and single molecule fluorescence fluctuation measurements will be employed to monitor how APS evolve from diffusible oligomers to large inclusions and quantitative proteomics will define signatures for cells with different forms of aggregates.2. To identify the mechanisms of aggregation toxicity through a systematic interactome analysis of APS in cell culture and mouse brain. The cellular localization of APS and their potential association with membrane structures and cellular machinery will be determined by cryo-ET.3. To elucidate why cellular protein quality control fails in neurodegenerative disease. Specially designed proteostasis sensors will be used to monitor the status of the protein folding machinery as aggregate pathol¬ogy develops. The potentially protective pathways of inclusion body formation will be explored using cryo-ET and laser capture dissection coupled with highly sensitive proteomics.Understanding aggregation toxicity will be invaluable in developing novel therapeutic strategies for some of the most debilitating diseases of our time. Champ scientifique natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicineneurologydementiaalzheimernatural sciencesphysical sciencesopticsmicroscopyelectron microscopynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-2012-SyG - ERC Synergy Grant Appel à propositions ERC-2012-SyG Voir d’autres projets de cet appel Régime de financement ERC-SyG - Synergy grant Chercheur en chef Franz-Ulrich Hartl Prof. Coordinateur MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Contribution de l’UE € 13 927 098,00 Adresse Hofgartenstrasse 8 80539 Munchen Allemagne Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Research Organisations Contact administratif Anne Katrin Werenskiold (Dr.) Chercheur principal Paul Wolfgang Baumeister (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Allemagne Contribution de l’UE € 13 927 098,00 Adresse Hofgartenstrasse 8 80539 Munchen Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Research Organisations Contact administratif Anne Katrin Werenskiold (Dr.) Chercheur principal Paul Wolfgang Baumeister (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée