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

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

doi:10.1111/acel.13005

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.

Highlights

There is a progressive decline in 26S proteasome function in the nervous system of mammals (Keller, Hanni, & Markesbery, 2000) as well as flies (Figure 1a), with a corresponding increase in 20S proteasome levels but not activity, which either declines or is unchanged (Figure 1a; Keller et al, 2000; Tonoki et al, 2009; Vernace, Arnaud, Schmidt‐Glenewinkel, & Figueiredo‐Pereira, 2007)
It has been shown that proteasome depletion and inhibition in mice can mirror brain aging phenotypes, producing neurodegeneration, cognitive deficits, and formation of Lewy‐like bodies (Bedford et al, 2008; Romero‐Granados, Fontan‐ Lozano, Aguilar‐Montilla, & Carrion, 2011)
To establish whether age‐related cognitive decline can be amelio‐ rated by augmenting proteasome function

Summary

Introduction

There is a progressive decline in 26S proteasome function in the nervous system of mammals (Keller, Hanni, & Markesbery, 2000) as well as flies (Figure 1a), with a corresponding increase in 20S proteasome levels but not activity, which either declines or is unchanged (Figure 1a; Keller et al, 2000; Tonoki et al, 2009; Vernace, Arnaud, Schmidt‐Glenewinkel, & Figueiredo‐Pereira, 2007). To establish whether age‐related cognitive decline can be amelio‐ rated by augmenting proteasome function. Overexpression of Prosβ5 posteclosion increased mRNA of other core proteasome subunits (Figure 1b), enhanced proteasome assembly (Figure 1c and Figure S1) and activity (Figure 1d), and in‐ creased oxidative stress resistance (Figure 1e), independent of ar‐ tifacts from RU486 treatment (Figure S2).

Objectives

Results

Conclusion