Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Abstract

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to posttranscriptional mechanisms that account for over 40% of the ageregulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.

FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity

“…Conversely, an intact proteasome is correlated with extreme longevity in humans ( Chondrogianni et al, 2000 ), while proteasome activation can increase cellular and organismal lifespan, alleviate aggregation-related pathologies and enhance stemness ( Chondrogianni et al, 2000 ; Kapeta et al, 2010 ; Chondrogianni et al, 2015a ; Kapetanou et al, 2017 ). Interestingly, studies in brain have demonstrated the link between proteasome activity and aging ( Triplett et al, 2015 ; Kelmer Sacramento et al, 2020 ), while Tropea and co-workers have proposed the involvement of IIS in these processes ( Wrigley et al, 2017 ). Other studies on skeletal muscle atrophy have addressed the role of mammalian FoxOs in the positive regulation of ubiquitin ligases.…”

Analyzing Ribosome Remodeling in Health and Disease

“…To obtain more direct evidence for protein remodeling of ribosomes, one should directly measure RP abundances as a more direct approach for evaluating ribosome remodeling across different conditions, Figure 1a. Such analyses in cell lysates have suggested changes in the protein composition of ribosomes as budding yeast undergoes the diauxic shift, [55] during aging, [56,57] and upon LPS-stimulation of mouse dendritic cells. [58] In addition, RP analysis from cell lysates has shown that ribosomal transcripts exhibit slower elongation rates with decreased protein production relative to other transcripts with similar ribosome densities.…”

Nothobranchius annual killifishes

“…3 d) [ 22 , 23 ], regeneration [ 24 ], neurodegeneration [ 25 ], and heart and muscle biology [ 26 , 27 ]. At the molecular level, studies have focused on mitochondrial function [ 28 ], epigenetics [ 26 , 29 ], telomere attrition [ 30 ], lipid peroxidation [ 31 ], and expression changes at the genome-wide and proteome-wide levels [ 26 , 29 , 32 – 38 ]. These phenotypes are conserved to a significant degree between humans and N. furzeri [ 29 , 39 ] .…”

“…Nothobranchius fishes are convenient experimental models for life-long investigations on the effects of dietary and environmental manipulations. They are particularly suited to study the effects of compounds that can be administered via injections [ 38 ], with the food [ 40 ] or in the water [ 37 ] in the context of pharmacology or ecotoxicology. Similarly, long-term consequences of exposure to environmental toxins can be investigated.…”