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Reduced proteasome activity in the aging brainresults 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 / 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 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Nothobranchius Furzeri

TISSUE(S): Brain

SUBMITTER: Alessandro Ori

LAB HEAD: Alessandro Ori

PROVIDER: PXD012314 | Pride | 2020-06-19

REPOSITORIES: pride

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			Action	DRS
	170120_JMK_EKS_TMT10_MZM_5w_vs_12w_16frHpH.pdResult	Other
	170120_JMK_EKS_TMT10_MZM_5w_vs_12w_16frHpH.pdResultView	Other
	170120_JMK_EKS_TMT10_MZM_5w_vs_12w_16frHpH.pep.pep.xml	Pepxml
	170120_JMK_EKS_TMT10_MZM_5w_vs_12w_16frHpH_TargetPeptideSpectrumMatch.txt	Txt
	170120_JMK_EKS_TMT10_MZM_5w_vs_12w_16frHpH_fr1.raw	Raw

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