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): Yarrowia Lipolytica (candida Lipolytica) Pan Troglodytes (chimpanzee) Pinus Radiata (monterey Pine) Taeniopygia Guttata (zebra Finch) (poephila Guttata) Xenopus Laevis (african Clawed Frog) Saccharomyces Cerevisiae (baker's Yeast) Merluccius Bilinearis (silver Hake) Sus Scrofa Domesticus (domestic Pig) Pongo Pygmaeus (bornean Orangutan) Struthio Camelus (ostrich) Staphylococcus Aureus Ricinus Communis Trypanosoma Brucei Zea Mays (maize) Olea Europaea (common Olive) Rattus Norvegicus (rat) Pisum Sativum (garden Pea) Solanum Tuberosum (potato) Oryza Sativa (rice) Rattus Rattus (black Rat) Nothobranchius Furzeri Triticum Aestivum (wheat) Mesocricetus Auratus (golden Hamster) Vigna Mungo (rice Bean) (black Gram) Nicotiana Tabacum (common Tobacco) Vitis Vinifera (grape) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Erika Kelmer Sacramento  

LAB HEAD: Alessandro Ori

PROVIDER: PXD016587 | Pride | 2020-06-22

REPOSITORIES: Pride