Landscape of protein aggregation and quality control in vertebrate aging and a case study on prion-like aggregation
Abstract/Contents
- Abstract
- Protein aggregation is a hallmark of age-related neurodegeneration. Yet whether aggregation drives age-related dysfunction and disease in other tissues is poorly understood. Here, I developed a method to isolate protein aggregates and leveraged the African turquoise killifish to obtain a systematic understanding of protein aggregation in seven tissues in an aging vertebrate. Interestingly, patterns of age-dependent aggregation were highly tissue-specific and not simply driven by tissue-specific protein expression. Age- and tissue-specificity of protein aggregation is linked to both protein autonomous biophysical features and selective alterations in protein quality control. Co-aggregation of protein quality control machineries during aging further reduces the proteostatic capacity and may contribute to aggregate burden in a feed-forward loop. Many age-related protein aggregates were associated with diseases of age, and diseases not previously linked to protein misfolding. In the aging brain, the enrichment of prion-like domains is a prominent feature among proteins with age-associated increases in aggregation. DDX5, an RNA helicase that is also involved in tau splicing, is one such protein that aggregates more in both old killifish and mice. DDX5 acts as bona fide prions in yeast. In vitro, DDX5 coacervates readily under physiological conditions, and the condensed state has enhanced activity than the diffuse state. Thus prion-like low complexity sequences make functionally advantageous coacervate more accessible at a cost of increased misfolded self-assembly that might contribute to cognitive decline during aging
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Chen, Yiwen |
|---|---|
| Degree supervisor | Jarosz, Daniel |
| Thesis advisor | Jarosz, Daniel |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Ferrell, James Ellsworth |
| Thesis advisor | Mochly-Rosen, Daria |
| Degree committee member | Brunet, Anne, 1972- |
| Degree committee member | Ferrell, James Ellsworth |
| Degree committee member | Mochly-Rosen, Daria |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Yiwen (Rachel) Chen |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Yiwen Chen
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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