Neuronal-specific proteasome augmentation via Prosβ5 overexpression extends lifespan and reduces age-related cognitive decline

Erin Munkácsy, E. Sandra Chocron, Laura Quintanilla, Christi M. Gendron, Scott D. Pletcher, Andrew M. Pickering

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Cognitive function declines with age throughout the animal kingdom, and increasing evidence shows that disruption of the proteasome system contributes to this deterioration. The proteasome has important roles in multiple aspects of the nervous system, including synapse function and plasticity, as well as preventing cell death and senescence. Previous studies have shown neuronal proteasome depletion and inhibition can result in neurodegeneration and cognitive deficits, but it is unclear if this pathway is a driver of neurodegeneration and cognitive decline in aging. We report that overexpression of the proteasome β5 subunit enhances proteasome assembly and function. Significantly, we go on to show that neuronal-specific proteasome augmentation slows age-related declines in measures of learning, memory, and circadian rhythmicity. Surprisingly, neuronal-specific augmentation of proteasome function also produces a robust increase of lifespan in Drosophila melanogaster. Our findings appear specific to the nervous system; ubiquitous proteasome overexpression increases oxidative stress resistance but does not impact lifespan and is detrimental to some healthspan measures. These findings demonstrate a key role of the proteasome system in brain aging.

Original languageEnglish (US)
Article numbere13005
JournalAging cell
Volume18
Issue number5
DOIs
StatePublished - Oct 1 2019

Keywords

  • Drosophila
  • aging
  • neurodegeneration
  • proteasome

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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