Objectif Parkinson's disease is a severe human neurodegenerative disorder that affects mainly the aging generation. It is characterized by the loss of dopaminergic neurons from the substantia nigra, and the formation Lewy bodies, intraneuronal inclusions which are primarily composed of fibrillar alpha-synuclein. Several lines of evidence support a role for molecular chaperones as modulators of alpha-synuclein aggregation and toxicity in Parkinson's disease. Current findings suggest that prevention and/or the reversion of alpha-synuclein aggregation by molecular chaperones may constitute a promising therapeutic approach for the treatment of Parkinson’s disease and related disorders. However, the molecular and structural bases underlying the mechanisms by which molecular chaperones modulate protein aggregation and amyloid formation are yet poorly understood. The overall objective of this proposal is to gain a detailed mechanistic insight into the structural and molecular mechanisms by which molecular chaperones modulate protein aggregation and neurotoxicity in vitro using cellular models of synucleinopathies. We will focus on the functional relationship of the molecular chaperones Hsp70, Hsp40, Hsp90, and, Hsp27 that have been linked to Parkinson’s disease. In addition, we will assay the impact of Hsp104, which is the protein disaggregation machinery from yeast, on alpha-synuclein aggregation and toxicity. Thereby, we will seek to elucidate the molecular mechanisms by which molecular chaperones interact with alpha-synuclein and modulate its structural and aggregation properties in vitro, and we will probe the ability of molecular chaperones to prevent and/or rescue alpha-synuclein cytotoxicity in cellular models of synucleinopathies, including primary neuronal cell cultures. Such a detailed understanding of the molecular mechanisms by which cytosolic chaperones modulate alpha-synuclein aggregation and toxicity could provide viable targets for therapeutic strategies. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineneurologyparkinson Mots‑clés Health sciences Hsp104 Hsp27 Hsp70/Hsp40 Hsp90 Natural sciences Neurodegenerative Diseases alpha-synuclein disaggregation molecular chaperones neuronal cell death protein aggregation Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) PEOPLE-2007-2-1.IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Appel à propositions FP7-PEOPLE-2007-2-1-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE Contribution de l’UE € 178 163,71 Adresse BATIMENT CE 3316 STATION 1 1015 Lausanne Suisse Voir sur la carte Région Schweiz/Suisse/Svizzera Région lémanique Vaud Type d’activité Higher or Secondary Education Establishments Contact administratif Laure Dayer (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
