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/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.

(Note: With the exception of the correction of typographical or spelling errors that could be a source of ambiguity, letters and reports are not edited. Depending on transfer agreements, referee reports obt ained elsewhere may or may not be included in this compilat ion. Referee report s are anonymous unless the Referee chooses to sign their report s.) 27th Mar 2020 1st Editorial Decision Thank you again for submit ting your work to Molecular Syst ems Biology. The rev iews from the other journal were quit e const ruct ive so as we discussed previously, we decided to use these report s rat her than rev iewing the st udy from scrat ch. Thank you for the det ailed and really wellst ruct ured point by point response, it made it easy for me to evaluat e the changes. I feel that the responses to the rev iewers' comment s seem to sat isfact orily address the point s raised. As most of the rev iewers' concerns referred to the need to provide furt her support for the main conclusions, but there were no serious concerns on the technical aspect s of the core experiment s report ed in the st udy, we have decided to proceed wit h making a decision based on our evaluat ion of the st udy and your responses.
Overall, we think that the in vivo prot easome inhibit or experiment s provide addit ional support for the proposed role of the prot easome. Similarly the MS analysis of aggregat es from young vs old mouse brains and the immunost aining in fish brain samples provide furt her support for the relat ed conclusions. Several ot her comment s referred to the need to include clarificat ions, text edit s, met hodological det ails and st at ist ical support and we think that they have been sat isfact orily addressed.
In summary, we think that the explanat ions and addit ional analyses performed in response to the rev iewers' comment s are sat isfact ory. As such, we have decided to proceed wit h the publicat ion of your st udy in Molecular Syst ems Biology, pending some minor rev isions list ed below: 3. Were any steps taken to minimize the effects of subjective bias when allocating animals/samples to treatment (e.g. randomization procedure)? If yes, please describe.
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For animal experiment (in vivo proteasome inhibitor), sample size was determined on the basis of the results of a pilot experiment.
No sample was excluded from the analysis For animal experiment (in vivo proteasome inhibitor), animals were randomly allocated to the different experimental groups. For animal experiment (in vivo proteasome inhibitor), animals were randomly allocated to the different experimental groups. No blinding of the investigator was performed when analysing the data.
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