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PreprintCited by 236Genetics, Aging, and Longevity in Model OrganismsUbiquitin and proteasome pathwaysAutophagy in Disease and Therapy

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

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Sacramento, Erika Kelmer, Kirkpatrick, Joanna M., Mazzetto, Mariateresa, Baumgart, Mario, Bartolome, Aleksandar, Di Sanzo, Simone, Caterino, Cinzia, Sanguanini, Michele, Papaevgeniou, Nikoletta, Lefaki, Maria, Childs, Dorothee, Bagnoli, Sara, Tozzini, Eva Terzibasi, Di Fraia, Domenico, Romanov, Natalie, Sudmant, Peter, Huber, Wolfgang, Chondrogianni, Niki, Vendruscolo, Michele, Cellerino, Alessandro, Ori, Alessandro·2019·Molecular Systems Biology
DOI 10.1101/577478PMC PMC7301280

Preprint — published as 10.15252/msb.20209596 · Paper page

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Abstract

Summary: 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 / dis-assembly 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 the 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: Progressive loss of stoichiometry affects multiple protein complexes Ribosomes aggregate in old brains Partial reduction of proteasome activity is sufficient to induce loss of stoichiometry Reduced proteasome levels are a major risk factor for early death in killifish

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Metadata

Authors
Sacramento, E. K., Kirkpatrick, J. M., Mazzetto, M., Baumgart, M., Bartolome, A., Di Sanzo, S., Caterino, C., Sanguanini, M., Papaevgeniou, N., Lefaki, M., Childs, D., Bagnoli, S., Tozzini, E. T., Di Fraia, D., Romanov, N., Sudmant, P., Huber, W., Chondrogianni, N., Vendruscolo, M., Cellerino, A., & Ori, A.
Affiliations
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
  • The Francis Crick Institute (GB)
  • Scuola Normale Superiore (IT)
  • University of Cambridge (GB)
  • National Hellenic Research Foundation (GR)
  • European Molecular Biology Laboratory (DE)
  • Max Planck Institute of Biophysics (DE)
  • University of California, Berkeley (US)
Corresponding author
Cellerino, Alessandro
ORCID
Venue
Molecular Systems Biology
Publisher
openRxiv
Published
2019-03-16
Volume
16
Issue
6
Pages
e9596-e9596
ISSN
1744-4292 (ISSN-L)
DOI
10.1101/577478
PMC
PMC7301280
OpenAlex
W3036344983
Cited by
236
References
2
Citations by year
2026: 42 · 2025: 32 · 2024: 40 · 2023: 48 · 2022: 24 · 2021: 36 · 2020: 13 · 2019: 1
FWCI
10.17
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Systems Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National Hellenic Research Foundation Helios Repository (National Hellenic Research Foundation) (submittedVersion, cc-by)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Scuola Normale Superiore di Pisa (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Deutsches Zentrum für Herz-Kreislaufforschung (81X2800193)
  • Australian Government
  • European Commission (T1EDK-00353)
  • Deutsche Forschungsgemeinschaft (GRK 2155, 2019_A79, 81X2800193)
  • Else Kröner-Fresenius-Stiftung (2019_A79)
  • Empirikeion Foundation
  • Leibniz-Gemeinschaft (81X2800193, GRK 2155, 2019_A79)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
brain aging, proteasome activity, proteostasis, protein aggregation, Nothobranchius furzeri, post-transcriptional regulation, mRNA-protein correlation, protein complex formation, age-related neurodegeneration, mortality risk factors, proteomics
MeSH terms
Aging, Animals, Brain, Cyprinodontiformes, Mice, Inbred C57BL, Ribosomal Proteins, Ribosomes, Risk Factors, RNA, Messenger, Reproducibility of Results, Proteasome Endopeptidase Complex, Biophysical Phenomena, Transcriptome, Protein Aggregates

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