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

Di Fraia, Domenico; Marino, Antonio; Lee, Jae Ho; Kelmer Sacramento, Erika; Baumgart, Mario; Bagnoli, Sara; Tomaz da Silva, Pedro; Kumar Sahu, Amit; Siano, Giacomo; Tiessen, Max; Terzibasi-Tozzini, Eva; Gagneur, Julien; Frydman, Judith; Cellerino, Alessandro; Ori, Alessandro

doi:10.1101/2023.07.20.549210

Cited by 3 publications

(4 citation statements)

References 115 publications

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“…Killifish MS data from (Di Fraia et al, 2023) were reanalysed with the same Spectronaut version using the same settings. DIA PTMs data were searched against their respective spectral library using Spectronaut Professional (18.2.33, Biognosys, Zurich, Switzerland).…”

Section: Discussionmentioning

confidence: 99%

“…Next, we investigated whether age-related alterations in ubiquitylation are conserved across different species by comparing our mouse dataset with one we previously generated for the short-lived killifish Nothobranchius furzeri (Di Fraia et al, 2023).…”

Section: Conserved Ubiquitylation Changes In the Aging Vertebrate Brainmentioning

confidence: 99%

“…Next, we aligned mouse and killifish ubiquitylated sites (see methods and Table S2). We compared age-related ubiquitylation changes in the two species upon correction for any underlying total protein differences that might confound the comparison (as described in (Di Fraia et al, 2023)). Of the 1640 sites we could align between mouse and killifish, 58% changed consistently or showed a consistent trend when relaxing filtering criteria (p<0.25 in both datasets, Figure 2A).…”

Section: Conserved Ubiquitylation Changes In the Aging Vertebrate Brainmentioning

confidence: 99%

“…Given the conservation of ubiquitin across evolution (Zuin et al, 2014), we asked whether the same alterations could be observed in different species. Thus, we turned to the short-lived Nothobranchius furzeri (killifish) because of its pronounced age-related neurodegeneration phenotypes, including accumulation of phosphorylated Tau with aging (de Bakker et al, 2023;Di Fraia et al, 2023;Louka et al, 2022). Notably, both mice and killifish exhibit an age-related accumulation of ubiquitin (Matsui et al, 2019;Ohtsuka et al, 1995) and a decline in proteasome activity (Burov et al, 2023;Kelmer Sacramento et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain

Marino,

Fraia,

Panfilova

et al. 2023

Preprint

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Post-translational modifications (PTMs) regulate protein homeostasis and function. How aging affects the landscape of PTMs remains largely elusive. Here, we reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the aging brain of mice. We show that aging has a major impact on protein ubiquitylation and that 29% of the ubiquitylation sites are affected independently of protein abundance, indicating altered PTM stoichiometry. We found a subset of these sites to be also affected in the brain of the short-lived killifishNothobranchius furzeri, highlighting a conserved aging phenotype. Furthermore, we estimated that over 35% of ubiquitylation changes observed in old mouse brains derive from partial proteasome inhibition, a well-established hallmark of brain aging. Our findings provide evidence of an evolutionarily conserved ubiquitylation signature of the aging brain and establish a causal link between proteasome inhibition and age-related remodeling of the ubiquitylome.

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Section: Discussionmentioning

confidence: 99%

Section: Conserved Ubiquitylation Changes In the Aging Vertebrate Brainmentioning

confidence: 99%

Section: Conserved Ubiquitylation Changes In the Aging Vertebrate Brainmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain

Marino,

Fraia,

Panfilova

et al. 2023

Preprint

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Regulating translation in aging: from global to gene-specific mechanisms

Solyga,

Majumdar,

Besse

2024

EMBO Rep

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Aging is characterized by a decline in various biological functions that is associated with changes in gene expression programs. Recent transcriptome-wide integrative studies in diverse organisms and tissues have revealed a gradual uncoupling between RNA and protein levels with aging, which highlights the importance of post-transcriptional regulatory processes. Here, we provide an overview of multi-omics analyses that show the progressive uncorrelation of transcriptomes and proteomes during the course of healthy aging. We then describe the molecular changes leading to global downregulation of protein synthesis with age and review recent work dissecting the mechanisms involved in gene-specific translational regulation in complementary model organisms. These mechanisms include the recognition of regulated mRNAs by trans-acting factors such as miRNA and RNA-binding proteins, the condensation of mRNAs into repressive cytoplasmic RNP granules, and the pausing of ribosomes at specific residues. Lastly, we mention future challenges of this emerging field, possible buffering functions as well as potential links with disease.

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Amyloid beta precursor protein contributes to brain aging and learning decline in short-lived turquoise killifish (Nothobranchius furzeri)

de Bakker,

Mihaljević,

Gharat

et al. 2024

Preprint

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Amyloid beta (A-Beta) accumulation is associated with inflammation, neurodegeneration, and cognitive decline in the context of neurodegenerative diseases. However, its role during normal aging remains largely unexplored. In this study, we investigated the natural impact of A-Beta precursor protein (app) on the aging brain using a short-lived vertebrate model, the turquoise killifish (Nothobranchius furzeri). We identified amyloid precursor protein derivatives in the killifish brain across different age groups and found that pyroglutamated amyloid beta, a neurotoxic A-Beta variant, accumulates intra-neuronally in an age-dependent manner, co-localizing with the apoptosis marker TUNEL. To determine whether A-Beta contributes to spontaneous brain aging, we used CRISPR/Cas9 to generate an amyloid precursor protein a (appa) knock-out killifish strain. Notably, appa -/- mutants exhibited reduced cell death and inflammation, an overall younger proteome, as well as improved learning capacity in old age. Taken together, we found that A-Beta precursor protein broadly affects vertebrate brain aging, making it a promising target for anti-aging interventions.

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

Cited by 3 publications

References 115 publications

Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain

Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain

Regulating translation in aging: from global to gene-specific mechanisms

Amyloid beta precursor protein contributes to brain aging and learning decline in short-lived turquoise killifish (Nothobranchius furzeri)

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