Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans
- German Center for Neurodegenerative Diseases (DZNE), Germany
- University of Cambridge, United Kingdom
Abstract
Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3 and Figure supplements 1, 3, 4, 7, 8 and 9.
Article and author information
Author details
Amberley D Stephens
Michele Vendruscolo
Clemens F Kaminski
Funding
Deutsches Zentrum für Neurodegenerative Erkrankungen
- Della C David
Biotechnology and Biological Sciences Research Council (BB/R021805/1)
- Romain F Laine
European Commission (Marie Curie International Reintegration grant 322120)
- Della C David
Engineering and Physical Sciences Research Council
- Clemens F Kaminski
Wellcome (203249/Z/16/Z)
- Gabriele S Kaminski Schierle
Medical Research Council (MR/N012453/1)
- Gabriele S Kaminski Schierle
Alzheimer's Research UK (ARUK-PG2013-14)
- Gabriele S Kaminski Schierle
Infinitus China Ltd
- Clemens F Kaminski
- Gabriele S Kaminski Schierle
Alzheimer's Research UK (Travel grant)
- Amberley D Stephens
Biotechnology and Biological Sciences Research Council (BB/P027431/1)
- Romain F Laine
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,790
- views
-
- 855
- downloads
-
- 60
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans
eLife 8:e43059.
https://doi.org/10.7554/eLife.43059
Further reading
-
- Cell Biology
Existence of cilia in the last eukaryotic common ancestor raises a fundamental question in biology: how the transcriptional regulation of ciliogenesis has evolved? One conceptual answer to this question is by an ancient transcription factor regulating ciliary gene expression in both uni- and multicellular organisms, but examples of such transcription factors in eukaryotes are lacking. Previously, we showed that an ancient transcription factor X chromosome-associated protein 5 (Xap5) is required for flagellar assembly in Chlamydomonas. Here, we show that Xap5 and Xap5-like (Xap5l) are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either Xap5 or Xap5l display infertility, as a result of meiotic prophase arrest and sperm flagella malformation, respectively. Mechanistically, Xap5 positively regulates the ciliary gene expression by activating the key regulators including Foxj1 and Rfx families during the early stage of spermatogenesis. In contrast, Xap5l negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Our results provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.
-
- Cell Biology
Chemokine receptors are GPCRs that regulate the chemotactic migration of a wide variety of cells including immune and cancer cells. Most chemokine receptors contain features associated with the ability to stimulate G protein signaling during β-arrestin-mediated receptor internalization into endosomes. As endosomal signaling of certain non-GPCR receptors plays a major role in cell migration, we chose to investigate the potential role of endosomal chemokine receptor signaling on mechanisms governing this function. Applying a combination of pharmacological and cell biological approaches, we demonstrate that the model chemokine receptor CCR7 recruits G protein and β-arrestin simultaneously upon chemokine stimulation, which enables internalized receptors to activate G protein from endosomes. Furthermore, spatiotemporal-resolved APEX2 proteome profiling shows that endosomal CCR7 uniquely enriches specific Rho GTPase regulators as compared to plasma membrane CCR7, which is directly associated with enhanced activity of the Rho GTPase Rac1 and chemotaxis of immune T cells. As Rac1 drives the formation of membrane protrusions during chemotaxis, our findings suggest an important integrated function of endosomal chemokine receptor signaling in cell migration.
