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bioRxiv · 10.1101/2023.07.20.549210

A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction

Di Fraia, D.·Marino, A.·Lee, J. H.·Kelmer Sacramento, E.·Baumgart, M.·Bagnoli, S.·Tomaz da Silva, P.·Kumar Sahu, A.·Siano, G.·Tiessen, M.·Gagneur, J.·Frydman, J.·Cellerino, A.·Ori, A.
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Abstract

Aging and neurodegeneration entail diverse cellular and molecular hallmarks. Here, we studied the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We reveal that aging causes widespread reduction of proteins enriched in basic amino acids that is independent of mRNA regulation, and it is not due to impaired proteasome activity. Instead, we identify a cascade of events where aberrant translation pausing leads to reduced ribosome availability resulting in proteome remodeling independently of transcriptional regulation. Our research uncovers a vulnerable point in the aging brains biology - the biogenesis of basic DNA/RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity and the biosynthesis of macromolecules. One-Sentence SummaryTranslation pausing reshapes the aging brain proteome, revealing vulnerabilities in the biogenesis of nucleic-acid protein.

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Di Fraia, D., Marino, A., Lee, J. H., Kelmer Sacramento, E., Baumgart, M., Bagnoli, S., Tomaz da Silva, P., Kumar Sahu, A., Siano, G., Tiessen, M., Gagneur, J., Frydman, J., Cellerino, A., Ori, A.. 2023-07-24. A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction. https://doi.org/10.1101/2023.07.20.549210

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