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

Erika Kelmer Sacramento ,Wolfgang Huber ,Peter H Sudmant ,Natalie Romanov ,Mariateresa Mazzetto ,Simone Di Sanzo ,Cinzia Caterino ,Alessandro Cellerino ,Niki Chondrogianni ,Maria Lefaki ,Dorothee Childs ,Mario Baumgart ,Michele Sanguanini ,Joanna Kirkpatrick ,Michele Vendruscolo ,Aleksandar Bartolome ,Nikoletta Papaevgeniou ,Eva Terzibasi Tozzini ,Sara Bagnoli ,Domenico Di Fraia ,Alessandro Ori

doi:10.15252/msb.20209596

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 post‐transcriptional mechanisms that account for over 40% of the age‐regulated 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.

Highlights

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration
In order to achieve higher proteome coverage, we split the age groups into two separate experiments based on tandem mass tag (TMT) multiplexing, where we compared adult vs young fish and old vs adult fish (Fig EV1A)
Recording of deaths starts at age of 5 wph, which corresponds to sexual maturity, and the colored dashed lines indicate the three age groups analyzed in this study, namely 5 weeks post-hatching, 12 wph, and 39 wph of a wild-derived strain that exhibits a median lifespan of 7–8 months

Summary

Introduction

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 post-transcriptional mechanisms that account for over 40% of the age-regulated 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. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of agerelated neurodegeneration

Methods

Results

Conclusion