Objectif Propagation of a species requires periodic cell renewal to avoid clonal senescence. Mylaboratory has described a new mechanism for such cell renewal in yeast, in which damagedprotein aggregates are transported out of the daughter buds along actin cables to preserveyouthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified thepolarisome as the machinery required for mitotic segregation and translocation of proteinaggregates. In addition, we found that the fusion of smaller aggregates into large inclusionbodies, a process that has been suggested to reduce the toxicity of such aggregates, requiresactin cables and their nucleation at the septin ring. Sir2p controls damage segregation byaffecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding andpolymerization. Considering that CCT has been implicated in mitigatingaggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables isaffecting formation, fusion, and resolution of aggregates, we hypothesize that CCTdeacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficialeffects in several neurodegenerative disorders caused by proteotoxic aggregates. This projectis aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how thecell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and thepolarity machinery. This will be accomplished by combining the power of synthetic geneticarray analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics.Using such approaches, the project seeks to decipher the machineries of the spatial qualitycontrol network as a means to identify new therapeutic targets that may retard or postponethe development of age-related maladies, including neurodegenerative disorders. Champ scientifique natural sciencesphysical sciencesclassical mechanicsfluid mechanicsmicrofluidicsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsgenomes 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-AG-LS3 - ERC Advanced Grant - Cellular and Developmental Biology Appel à propositions ERC-2010-AdG_20100317 Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil GOETEBORGS UNIVERSITET Contribution de l’UE € 2 371 262,00 Adresse VASAPARKEN 405 30 Goeteborg Suède Voir sur la carte Région Södra Sverige Västsverige Västra Götalands län Type d’activité Higher or Secondary Education Establishments Chercheur principal Lars Bertil Thomas Nyström (Prof.) Contact administratif Ludde Edgren (Dr.) 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 GOETEBORGS UNIVERSITET Suède Contribution de l’UE € 2 371 262,00 Adresse VASAPARKEN 405 30 Goeteborg Voir sur la carte Région Södra Sverige Västsverige Västra Götalands län Type d’activité Higher or Secondary Education Establishments Chercheur principal Lars Bertil Thomas Nyström (Prof.) Contact administratif Ludde Edgren (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée