%0 Journal Article %A Erika Kelmer Sacramento %A Joanna M. Kirkpatrick %A Mariateresa Mazzetto %A Simone Di Sanzo %A Cinzia Caterino %A Michele Sanguanini %A Nikoletta Papaevgeniou %A Maria Lefaki %A Dorothee Childs %A Sara Bagnoli %A Eva Terzibasi Tozzini %A Aleksandar Bartolome %A Natalie Romanov %A Mario Baumgart %A Wolfgang Huber %A Niki Chondrogianni %A Michele Vendruscolo %A Alessandro Cellerino %A Alessandro Ori %T Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation %D 2019 %R 10.1101/577478 %J bioRxiv %P 577478 %X 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 by using the short-lived vertebrate Nothobranchius furzeri and combining transcriptomics, proteomics and thermal proteome profiling. We found that the correlation between protein and mRNA levels is progressively reduced during aging, and that post-transcriptional mechanisms are responsible for over 40% of these alterations. These changes induce a progressive stoichiometry loss in protein complexes, including ribosomes, which have low thermal stability in brain lysates and whose component proteins are enriched in aggregates found in old brains. Mechanistically, we show that reduced proteasome activity occurs early during brain aging, and is sufficient to induce loss of stoichiometry. Our work thus defines early events in the aging process that can be targeted to prevent loss of protein homeostasis and age-related neurodegeneration.HighlightsTimeline of proteome changes during killifish brain agingProgressive loss of stoichiometry affects multiple protein complexesRibosomes have low thermal stability and aggregate in old brainsPartial reduction of proteasome activity is sufficient to induce loss of stoichiometry %U https://www.biorxiv.org/content/biorxiv/early/2019/03/16/577478.full.pdf