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Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

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.

2024-01-09 systems biology
10.1101/2023.07.20.549210 bioRxiv
Show 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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