Objective 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. Fields of science 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) Topic(s) ERC-AG-LS3 - ERC Advanced Grant - Cellular and Developmental Biology Call for proposal ERC-2010-AdG_20100317 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution GOETEBORGS UNIVERSITET EU contribution € 2 371 262,00 Address VASAPARKEN 405 30 Goeteborg Sweden See on map Region Södra Sverige Västsverige Västra Götalands län Activity type Higher or Secondary Education Establishments Principal investigator Lars Bertil Thomas Nyström (Prof.) Administrative Contact Ludde Edgren (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all GOETEBORGS UNIVERSITET Sweden EU contribution € 2 371 262,00 Address VASAPARKEN 405 30 Goeteborg See on map Region Södra Sverige Västsverige Västra Götalands län Activity type Higher or Secondary Education Establishments Principal investigator Lars Bertil Thomas Nyström (Prof.) Administrative Contact Ludde Edgren (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data