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Spatial protein quality control and its links to aging, proteotoxicity, and polarity (QualiAGE)
Start date: Jun 1, 2011, End date: May 31, 2016 PROJECT  FINISHED 

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.

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