Journal article
Stable Isotope Labeling Reveals Novel Insights Into Ubiquitin-Mediated Protein Aggregation With Age, Calorie Restriction, and Rapamycin Treatment
The journals of gerontology. Series A, Biological sciences and medical sciences, Vol.73(5), pp.561-570
04/17/2018
DOI: 10.1093/gerona/glx047
PMCID: PMC6380815
PMID: 28958078
Abstract
Accumulation of protein aggregates with age was first described in aged human tissue over 150 years ago and has since been described in virtually every human tissue. Ubiquitin modifications are a canonical marker of insoluble protein aggregates; however, the composition of most age-related inclusions remains relatively unknown. To examine the landscape of age-related protein aggregation in vivo, we performed an antibody-based pulldown of ubiquitinated proteins coupled with metabolic labeling and mass spectrometry on young and old mice on calorie restriction (CR), rapamycin (RP)-supplemented, and control diets. We show increased abundance of many ubiquitinated proteins in old mice and greater retention of preexisting (unlabeled) ubiquitinated proteins relative to their unmodified counterparts-fitting the expected profile of age-increased accumulation of long-lived aggregating proteins. Both CR and RP profoundly affected ubiquitinome composition, half-live, and the insolubility of proteins, consistent with their ability to mobilize these age-associated accumulations. Finally, confocal microscopy confirmed the aggregation of two of the top predicted aggregating proteins, keratins 8/18 and catalase, as well as their attenuation by CR and RP. Stable-isotope labeling is a powerful tool to gain novel insights into proteostasis mechanisms, including protein aggregation, and could be used to identify novel therapeutic targets in aging and protein aggregation diseases.
Details
- Title: Subtitle
- Stable Isotope Labeling Reveals Novel Insights Into Ubiquitin-Mediated Protein Aggregation With Age, Calorie Restriction, and Rapamycin Treatment
- Creators
- Nathan B Basisty - Buck Institute for Research on Aging, Novato, CaliforniaYuxin Liu - Department of Medicine, SUNY Upstate Medical University, Syracuse, New YorkJason Reynolds - Department of Medicine, University of Washington, SeattlePabalu P Karunadharma - The Scripps Research Institute, Jupiter, FloridaDao-Fu Dai - Department of Pathology, University of Iowa Carver College of Medicine, Iowa CityJeanne Fredrickson - Department of Pathology, University of Washington, SeattleRichard P Beyer - Department of Environmental Health, University of Washington, SeattleMichael J MacCoss - Department of Genome Sciences, University of Washington, SeattlePeter S Rabinovitch - Department of Pathology, University of Washington, Seattle
- Resource Type
- Journal article
- Publication Details
- The journals of gerontology. Series A, Biological sciences and medical sciences, Vol.73(5), pp.561-570
- Publisher
- United States
- DOI
- 10.1093/gerona/glx047
- PMID
- 28958078
- PMCID
- PMC6380815
- ISSN
- 1079-5006
- eISSN
- 1758-535X
- Grant note
- P41 GM103533 / NIGMS NIH HHS P01 AG001751 / NIA NIH HHS S10 OD016240 / NIH HHS T32 AG000057 / NIA NIH HHS P30 AG013280 / NIA NIH HHS R01 HL101186 / NHLBI NIH HHS R01 AG038550 / NIA NIH HHS
- Language
- English
- Date published
- 04/17/2018
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984070846302771
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