Links between Aging and Proteostasis Decline in Saccharomyces cerevisiae

Sammanfattning: Proteins are continuously synthesized and degraded to meet the demands of the cell. Hence, a proper balance between synthesis, folding, disaggregation and degradation is of essence to ensure cell survival. Disruption of any part of this proteostasis network may have severe consequences for cellular fitness and longevity. This thesis focuses on how proteostasis decline and aggregate-management is linked to aging in the yeast Saccharomyces cerevisiae and why aggregates accumulate in the yeast mother cells. The study revealed that three complementary processes are involved in this process; (i) mother cell-biased segregation of aggregated proteins during cytokinesis, (ii) - Text removed from public version - (iii) an age-related decline in proteasome function. The first process explains why aggregates, once formed, by necessity must accumulate in aging mother cells. This asymmetric inheritance is the result of Hsp104-containing aggregates associating with the actin cytoskeleton, which effectively hinders movement of aggregates into the daughter cell. In addition, actin-tethered aggregates display retrograde transport towards the mother cell providing the daughter cell with the means of clearing itself of aggregates. But why do aggregates form upon cellular aging? The data presented herein indicate that - Text removed from public version - The third process underlying aggregate accumulation includes a functional decline of the ubiquitin-proteasome-system, UPS. Experiments using a model in vivo UPS-substrate revealed that 26S proteasome function is greatly diminished in aged cells, an impediment which can be restored by elevating protein disaggregation. The data suggest that the accrual of aggregated proteins obstructs proper UPS function resulting in a negative proteostasis feedback loop. Finally, - Text removed from public version - and proteasome function generated an extension in lifespan, enhanced disaggregation does not, suggesting that it may be more beneficial for the cell to prevent aggregates from forming than eliminating the ones already formed. Thus, aggregate-precursors may be the initial culprits in age-associated proteostasis decline. Key words: Aging, Aggregates, Proteostasis, Proteasome, disaggregation, Peroxiredoxins, Asymmetric inheritance, S. cerevisiae