A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease
Open accessAbstract
Chaperones are central to the proteostasis network (PN) and safeguard the proteome from misfolding, aggregation, and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression data sets. During human brain aging, expression of 32% of the chaperome, corresponding to ATP-dependent chaperone machines, is repressed, whereas 19.5%, corresponding to ATP-independent chaperones and co-chaperones, are induced. These repression and induction clusters are enhanced in the brains of those with Alzheimer's, Huntington's, or Parkinson's disease. Functional properties of the chaperome were assessed by perturbation in C. elegans and human cell models expressing Aβ, polyglutamine, and Huntingtin. Of 219 C. elegans orthologs, knockdown of 16 enhanced both Aβ and polyQ-associated toxicity. These correspond to 28 human orthologs, of which 52% and 41% are repressed, respectively, in brain aging and disease and 37.5% affected Huntingtin aggregation in human cells. These results identify a critical chaperome subnetwork that functions in aging and disease.
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In the aging brain, small HSPs show increased transcription, whereas most other major chaperones are reduced.
“Notably, small HSPs are also transcriptionally induced in the aging brain, while most other major chaperone components are down-regulated (Brehme et al., 2014).”
From Widespread Proteome Remodeling and Aggregation in Aging C. elegans (2015) · cites this paper as Brehme et al., 2014
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- Authors
- Brehme, M., Voisine, C., Rolland, T., Wachi, S., Soper, J. H., Zhu, Y., Orton, K., Villella, A., Garza, D., Vidal, M., Ge, H., & Morimoto, R. I.
- Affiliations
- Northwestern University (US)
- Harvard University (US)
- Proteostasis Therapeutics (United States) (US)
- Corresponding author
- Vidal, Marc
- Ge, Hui
- Morimoto, Richard I.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 9
- Issue
- 3
- Pages
- 1135-1150
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4255334
- OpenAlex
- W2122674036
- Cited by
- 584
- References
- 64
- Citations by year
- 2026: 48 · 2025: 46 · 2024: 52 · 2023: 58 · 2022: 58 · 2021: 58 · 2020: 60 · 2019: 54 · 2018: 50 · 2017: 43 · 2016: 32 · 2015: 24
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute on Aging (R37AG026647, R01AG026647)
- National Institute of Mental Health
- National Human Genome Research Institute (P50HG004233)
- National Cancer Institute (P30CA060553)
- National Institute of General Medical Sciences (R01GM038109, R37GM038109)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- proteostasis network, brain aging, neurodegenerative diseases, Alzheimer's disease, Huntington's disease, Parkinson's disease, molecular chaperones, protein misfolding, protein aggregation, proteotoxicity, ATP-dependent chaperones, ATP-independent chaperones, co-chaperones, amyloid-beta, polyglutamine, huntingtin aggregation
- MeSH terms
- Huntingtin Protein, Aging, Animals, Brain, Disease Models, Animal, Humans, Models, Biological, Nerve Tissue Proteins, Caenorhabditis elegans, Protein Folding, Molecular Chaperones, Neurodegenerative Diseases, Gene Regulatory Networks, Proteostasis Deficiencies, Protein Aggregation, Pathological
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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