Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate

Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. A...

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Bibliographic Details
Published inDevelopmental cell Vol. 59; no. 14; pp. 1892 - 1911.e13
Main Authors Chen, Yiwen R., Harel, Itamar, Singh, Param Priya, Ziv, Inbal, Moses, Eitan, Goshtchevsky, Uri, Machado, Ben E., Brunet, Anne, Jarosz, Daniel F.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 22.07.2024
Subjects
aggregates
aging
Aging - metabolism
Animals
Humans
multi-tissue
Organ Specificity
Progeria - genetics
Progeria - metabolism
Progeria - pathology
Protein Aggregates
Protein Aggregation, Pathological - metabolism
protein homeostasis
proteomics
Proteostasis
systems biology
Vertebrates - metabolism
systems biology
aggregates
multi-tissue
aging
proteomics
protein homeostasis
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Summary:Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue specific and not simply driven by protein expression differences. Experimental interrogation in killifish and yeast, combined with machine learning, indicates that this specificity is linked to protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when mutated, drive human diseases. Our data chart a comprehensive landscape of protein aggregation during vertebrate aging and identify strong, tissue-specific associations with dysfunction and disease. [Display omitted] •Tissue-specific protein aggregation is common during vertebrate aging•Biophysical properties and the decline in tissue-specific proteostasis impact these patterns•Aggregation increases in tissues subject to accelerated aging in telomerase mutants•Many proteins that aggregate during physiological aging are linked to disease Chen and Harel use quantitative proteomics to profile protein aggregation in several vertebrate tissues during aging, finding that age-related protein aggregation is highly tissue specific, in part due to tissue-selective defects in protein quality control. Many disease proteins form age-related protein aggregates, potentially contributing to tissue defects during aging.
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AUTHOR CONTRIBUTIONS
Y.R.C., I.H., A.B., and D.F.J. designed this study with initial help from I.Z. I.H. isolated killifish organs, and Y.R.C. and I.Z. isolated samples for mass spectrometry analysis with the help of I.H. and did silver stain analysis. Y.R.C designed and implemented mass spectrometry data analysis with input from I.H., P.P.S., A.B. and D.F.J. Y.R.C. constructed yeast strains expressing killifish proteins with help from I.H. and B.E.M. and quantified yeast microscopy images. Y.R.C. performed protein feature analysis and built machine learning models. P.P.S. performed GSEA analysis and calculated the evolutionary rate of killifish proteins. P.P.S. and Y.R.C. conducted independent code check on the analysis. E.M. and U.G. performed the FUCCI FACS analysis under the guidance of I.H. Y.R.C., I.H., A.B., and D.F.J. wrote the manuscript, and all the authors commented on the manuscript.
ISSN:1534-5807
1878-1551
1878-1551
DOI:10.1016/j.devcel.2024.04.014