Abstract
The activity of the ubiquitin-proteasome system, UPS, declines during aging in several multicellular organisms. The reason behind this decline remains elusive. Here, using yeast as a model system, we show that while the level and potential capacity of the 26S proteasome is maintained in replicatively aged cells, the UPS is not functioning properlyin vivo. As a consequence cytosolic UPS substrates, such as ΔssCPY* are stabilized, accumulate, and form inclusions. By integrating a pGPD-HSP104 recombinant gene into the genome, we were able to constitutively elevate protein disaggregase activity, which diminished the accumulation of protein inclusions during aging. Remarkably, this elevated disaggregation restored degradation of a 26S proteasome substrate in aged cells without elevating proteasome levels, demonstrating that age-associated aggregation obstructs UPS function. The data supports the existence of a negative feedback loop that accelerates aging by exacerbating proteostatic decline once misfolded and aggregation-prone proteins reach a critical level.
Highlights
The activity of the ubiquitin‐proteasome system, ubiquitin-dependent system (UPS), declines during aging in several multicellular organisms
A UPS substrate accumulates and aggregates upon yeast replicative aging The ∆ssCPY*-GFP fusion contains a mutated form of the carboxypeptidase YscY that misfolds in the cytoplasm but is rapidly degraded by the UPS [20]. We used this protein construct to test if aging of yeast mother cells might lead to defects in UPS functions, which would result in the accumulation of misfolded ∆ssCPY* and its aggregation
As shown in figures 1D&E, there is a dramatic increase in ∆ssCPY*-GFP aggregate formation in these aged cells: While no aggregates could be detected in young cells, 50% of the aged cells harbored ∆ssCPY*-GFP foci (Fig. 1E)
Summary
The activity of the ubiquitin‐proteasome system, UPS, declines during aging in several multicellular organisms. By integrating a pGPD‐HSP104 recombinant gene into the genome, we were able to constitutively elevate protein disaggregase activity, which diminished the accumulation of protein inclusions during aging. This elevated disaggregation restored degradation of a 26S proteasome substrate in aged cells without elevating proteasome levels, demonstrating that age‐associated aggregation obstructs UPS function. The UPS has recently received special attention in aging research because a decline in UPS activity may explain why aging is a risk factor for neurodegenerative diseases [15] and since elevated UPS activity can extend life span.
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