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 proteo...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-06-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20209596 |
| _version_ | 1827014919722106880 |
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| author | Erika Kelmer Sacramento Joanna M Kirkpatrick Mariateresa Mazzetto Mario Baumgart Aleksandar Bartolome Simone Di Sanzo Cinzia Caterino Michele Sanguanini Nikoletta Papaevgeniou Maria Lefaki Dorothee Childs Sara Bagnoli Eva Terzibasi Tozzini Domenico Di Fraia Natalie Romanov Peter H Sudmant Wolfgang Huber Niki Chondrogianni Michele Vendruscolo Alessandro Cellerino Alessandro Ori |
| author_facet | Erika Kelmer Sacramento Joanna M Kirkpatrick Mariateresa Mazzetto Mario Baumgart Aleksandar Bartolome Simone Di Sanzo Cinzia Caterino Michele Sanguanini Nikoletta Papaevgeniou Maria Lefaki Dorothee Childs Sara Bagnoli Eva Terzibasi Tozzini Domenico Di Fraia Natalie Romanov Peter H Sudmant Wolfgang Huber Niki Chondrogianni Michele Vendruscolo Alessandro Cellerino Alessandro Ori |
| author_sort | Erika Kelmer Sacramento |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T18:00:05Z |
| format | Article |
| id | doaj.art-d0fdedc91a124678a4c4681ccc1e444c |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2025-02-18T14:15:34Z |
| publishDate | 2020-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-d0fdedc91a124678a4c4681ccc1e444c2024-10-28T09:16:50ZengSpringer NatureMolecular Systems Biology1744-42922020-06-0116612210.15252/msb.20209596Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregationErika Kelmer Sacramento0Joanna M Kirkpatrick1Mariateresa Mazzetto2Mario Baumgart3Aleksandar Bartolome4Simone Di Sanzo5Cinzia Caterino6Michele Sanguanini7Nikoletta Papaevgeniou8Maria Lefaki9Dorothee Childs10Sara Bagnoli11Eva Terzibasi Tozzini12Domenico Di Fraia13Natalie Romanov14Peter H Sudmant15Wolfgang Huber16Niki Chondrogianni17Michele Vendruscolo18Alessandro Cellerino19Alessandro Ori20Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Centre for Misfolding Diseases, Department of Chemistry, University of CambridgeInstitute of Chemical Biology, National Hellenic Research FoundationInstitute of Chemical Biology, National Hellenic Research FoundationEuropean Molecular Biology LaboratoryBio@SNS, Scuola Normale SuperioreBio@SNS, Scuola Normale SuperioreLeibniz Institute on Aging‐Fritz Lipmann Institute (FLI)European Molecular Biology LaboratoryUniversity of California BerkeleyEuropean Molecular Biology LaboratoryInstitute of Chemical Biology, National Hellenic Research FoundationCentre for Misfolding Diseases, Department of Chemistry, University of CambridgeLeibniz Institute on Aging‐Fritz Lipmann Institute (FLI)Leibniz Institute on Aging‐Fritz Lipmann Institute (FLI)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.https://doi.org/10.15252/msb.20209596aginglifespanproteomestoichiometrytranscriptome |
| spellingShingle | Erika Kelmer Sacramento Joanna M Kirkpatrick Mariateresa Mazzetto Mario Baumgart Aleksandar Bartolome Simone Di Sanzo Cinzia Caterino Michele Sanguanini Nikoletta Papaevgeniou Maria Lefaki Dorothee Childs Sara Bagnoli Eva Terzibasi Tozzini Domenico Di Fraia Natalie Romanov Peter H Sudmant Wolfgang Huber Niki Chondrogianni Michele Vendruscolo Alessandro Cellerino Alessandro Ori Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation Molecular Systems Biology aging lifespan proteome stoichiometry transcriptome |
| title | Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation |
| title_full | Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation |
| title_fullStr | Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation |
| title_full_unstemmed | Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation |
| title_short | Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation |
| title_sort | reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation |
| topic | aging lifespan proteome stoichiometry transcriptome |
| url | https://doi.org/10.15252/msb.20209596 |
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