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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Kelmer Sacramento, Erika  ORCID logo  https://orcid.org/0000-0002-3336-982X
Kirkpatrick, Joanna M 
Mazzetto, Mariateresa 
Baumgart, Mario 
Bartolome, Aleksandar 

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.

Description

Keywords

aging, lifespan, proteome, stoichiometry, transcriptome, Aging, Animals, Biophysical Phenomena, Brain, Cyprinodontiformes, Mice, Inbred C57BL, Proteasome Endopeptidase Complex, Protein Aggregates, RNA, Messenger, Reproducibility of Results, Ribosomal Proteins, Ribosomes, Risk Factors, Transcriptome

Journal Title

Mol Syst Biol

Conference Name

Journal ISSN

1744-4292
1744-4292

Volume Title

16

Publisher

Springer Science and Business Media LLC