Dataset Information

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 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 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Nothobranchius Furzeri

TISSUE(S): Brain

SUBMITTER: Erika Kelmer Sacramento

LAB HEAD: Alessandro Ori

PROVIDER: PXD016459 | Pride | 2020-06-22

REPOSITORIES: Pride

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			Action	DRS
	190923_EKS_NF_Bort_500uM_11.raw	Raw
	190923_EKS_NF_Bort_500uM_12.raw	Raw
	190923_EKS_NF_Bort_500uM_13.raw	Raw
	190923_EKS_NF_Bort_500uM_14.raw	Raw
	190923_EKS_NF_Bort_500uM_16.raw	Raw

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Publications

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

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

Molecular systems biology 20200601 6

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 ...[more]

PMID: 32558274

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