Obiettivo 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. Campo scientifico natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicineneurologydementiaalzheimernatural sciencesphysical sciencesopticsmicroscopyelectron microscopynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding Programma(i) 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) Argomento(i) ERC-2012-SyG - ERC Synergy Grant Invito a presentare proposte ERC-2012-SyG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-SyG - Synergy grant Primo ricercatore principale Franz-Ulrich Hartl Prof. Coordinatore MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Contributo UE € 13 927 098,00 Indirizzo Hofgartenstrasse 8 80539 Munchen Germania Mostra sulla mappa Regione Bayern Oberbayern München, Kreisfreie Stadt Tipo di attività Research Organisations Contatto amministrativo Anne Katrin Werenskiold (Dr.) Ricercatore principale Paul Wolfgang Baumeister (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Germania Contributo UE € 13 927 098,00 Indirizzo Hofgartenstrasse 8 80539 Munchen Mostra sulla mappa Regione Bayern Oberbayern München, Kreisfreie Stadt Tipo di attività Research Organisations Contatto amministrativo Anne Katrin Werenskiold (Dr.) Ricercatore principale Paul Wolfgang Baumeister (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato