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Spatial protein quality control and its links to aging, proteotoxicity, and polarity

Final Report Summary - QUALIAGE (Spatial protein quality control and its links to aging, proteotoxicity, and polarity)

Asymmetric cell division is key to cellular differentiation and one intriguing aspect of such asymmetry is that a young and immaculate cell can be generated from an aged and deteriorated one. In bacteria, yeast, and specific stem cells, the generation of such rejuvenated progeny includes an asymmetrical, inheritance of damaged and aggregated proteins in which the retention of such proteins in one cell ensures the longevity of the other. This control of damage inheritance is dependent on the spatial deposition of damaged proteins into specific quality control compartments within the cell and the formation of such compartments is a factor-dependent processes. However, how damaged and aged proteins are distinguished and sorted to the different compartments is not known. In addition, identification of Asymmetry-Generating Genes (AGGs) controlling the inheritance of damaged proteins has so far been restricted to candidate approaches.
In this project, we have developed an unbiased, high-throughput screen to identify AGGs and present a catalogue of an organism’s complement of genes involved in generating age-asymmetry. We discovered previously unknown genes required for recognizing, retaining, and spatially controlling damaged proteins in aged cells and found that some of those genes act as gerontogenes, in other words, genes that when modified can prolong the lifespan of the organism. Elucidating the function of such genes is believed to enable deciphering the driving forces of the aging process and holds the potential to find novel and early markers of importance for protecting the cells against cytotoxic disease proteins linked the neuropathologies, such as Alzheimer’s, Parkinson’s and Huntington’s diseases.