Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins
Open accessAbstract
The maintenance of protein solubility is a fundamental aspect of cellular homeostasis because protein aggregation is associated with a wide variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or aging. A crucial question in this context is why only certain proteins appear to aggregate readily in vivo, whereas others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. We find that these supersaturated proteins represent a metastable subproteome involved in pathological aggregation during stress and aging and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging.
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The high solubility of abundant proteins is insufficient to protect them from age-dependent aggregation, as they eventually exceed critical concentrations (supersaturation).
“Apparently, the high solubility of abundant proteins is insufficient to protect them from age-dependent aggregation, as eventually these proteins exceed their critical concentrations, a phenomenon referred to as ‘supersaturation’ (Ciryam et al., 2013).”
From Widespread Proteome Remodeling and Aggregation in Aging C. elegans (2015) · cites this paper as Ciryam et al., 2013
Proteome remodeling promotes aggregation by pushing some proteins above a solubility threshold, i.e., supersaturation.
“Importantly, proteome remodeling acts as a driver of aggregation by raising the level of a subset of proteins beyond a critical solubility limit (‘supersaturation’) (Ciryam et al., 2013) (Figure 7D).”
From Widespread Proteome Remodeling and Aggregation in Aging C. elegans (2015) · cites this paper as Ciryam et al., 2013
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- Authors
- Ciryam, P., Tartaglia, G. G., Morimoto, R. I., Dobson, C. M., & Vendruscolo, M.
- Affiliations
- Northwestern University (US)
- Universitat Pompeu Fabra (ES)
- University of Cambridge (GB)
- Corresponding author
- Morimoto, Richard I.
- Dobson, Christopher M.
- Vendruscolo, Michele
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 5
- Issue
- 3
- Pages
- 781-790
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3883113
- OpenAlex
- W2146554687
- Cited by
- 270
- References
- 66
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 14 · 2023: 29 · 2022: 29 · 2021: 29 · 2020: 16 · 2019: 28 · 2018: 22 · 2017: 20 · 2016: 18 · 2015: 25 · 2014: 18
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by)
- Funders
- Ellison Medical Foundation
- Wellcome Trust (089703)
- US-UK Fulbright Commission
- National Institutes of Health
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/H003843/1)
- National Institute on Aging (R37AG026647, R01AG026647)
- National Institute of General Medical Sciences (R01GM038109, R37GM038109)
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- protein aggregation, protein solubility, neurodegenerative diseases, aging, protein misfolding, protein abundance, cellular stress, proteostasis
- MeSH terms
- Humans, Proteins, Protein Folding, Neurodegenerative Diseases
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