Enhancing protein disaggregation restores proteasome activity in aged cells

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 properly in 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.

The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

“…Moreover, dietary administration of protein aggregates in young flies suppressed proteasome activity and caused premature aging (Tsakiri et al, 2013c). In line with these findings that indicate a significant effect of protein aggregation on proteasome functionality, overexpression of the Hsp104 disaggregase in yeast enhanced protein disaggregation and partially restored proteasome functionality and activities in aged cells (Andersson et al, 2013).…”

Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells

“…In this regard, the MAPS pathway might be required to remove substrates with defective degradation signals. Alternatively, the proteasome function is often overwhelmed by acute protein-misfolding stress [42][43][44] , necessitating additional stress-relieving pathways. Sequestration of misfolded proteins in aggregates for autophagic clearance might be an alternative mechanism to minimize damage by protein misfolding, but this strategy could lead to co-depletion of essential cellular factors trapped in aggregates.…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Proteasome dysfunction during ageing can occur at different levels such as decreased expression, alteration and/or replacement of proteasome subunits [33][34][35] , disassembly of proteasomes 36 or inactivation by interacting with protein aggregates 37,38 . This later mechanism could induce a catastrophic proteostasis feedback during ageing, since inhibition of proteostasis itself can induce the accumulation of protein inclusions, which in turn can obstruct and further inhibit proteasome activity 37 . A decline in proteasome function during ageing and senescence has been observed in several mammalian tissues and cells such as human skin, epidermal cells, fibroblasts and lymphocytes, bovine eye lens and rat liver, lung, heart, kidney, spinal cord, hippocampus, cerebral cortex and muscle tissues 39 .…”