Enhancing protein disaggregation restores proteasome activity in aged cells

Area of Science:

• Cellular biology
• Aging research
• Molecular mechanisms of aging

Background:

• The ubiquitin-proteasome system (UPS) activity declines with age in many organisms.
• The precise reasons for this age-related UPS decline are not fully understood.
• Maintaining proteasome levels does not guarantee UPS function in aged cells.

Purpose of the Study:

• To investigate the functional decline of the UPS in aged yeast cells.
• To determine the role of protein aggregation in age-associated UPS dysfunction.
• To explore therapeutic strategies targeting protein aggregation to restore UPS function.

Main Methods:

• Utilized yeast as a model organism for studying aging.
• Assessed the levels and capacity of the 26S proteasome in aged cells.
• Monitored the accumulation of UPS substrates and protein inclusions.
• Genetically engineered yeast with elevated protein disaggregase activity (HSP104).

Main Results:

• In aged yeast, the 26S proteasome levels were maintained, but UPS function was impaired in vivo.
• Cytosolic UPS substrates accumulated and formed inclusions in aged cells.
• Elevated protein disaggregase activity reduced protein inclusion formation.
• Restored UPS substrate degradation in aged cells without increasing proteasome levels.

Conclusions:

• Age-associated protein aggregation directly obstructs ubiquitin-proteasome system function.
• Protein disaggregation can rescue UPS function in aged cells.
• A negative feedback loop involving protein aggregation exacerbates age-related proteostatic decline.