The DOI matches its Crossref record; 29 of the 30 references it cites were found in a registry or an index.
Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases
Abstract
Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employed Caenorhabditis elegans polyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.
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“They have demonstrated the existence of a pool of metastable proteins in all cells, highly dependent on chaperones for their normal folding and function, and how these proteins can become unstable and aggregate in the presence of additional pathogenic proteins, such as those altered in protein conformational disorders (Gidalevitz et al., 2006).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Gidalevitz et al., 2006
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Adapting Proteostasis for Disease Intervention
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Metadata
- Authors
- Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R., & Morimoto, R. I.
- Affiliations
- Northwestern University (US)
- Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
- Corresponding author
- Gidalevitz, Tali
- Morimoto, Richard I.
- Venue
- Science
- Published
- 2006-03-10
- Volume
- 311
- Issue
- 5766
- Pages
- 1471-1474
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2025851491
- Cited by
- 643
- References
- 30
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 15 · 2023: 22 · 2022: 26 · 2021: 24 · 2020: 28 · 2019: 38 · 2018: 28 · 2017: 28 · 2016: 29 · 2015: 28 · 2014: 46 · 2013: 40 · 2012: 41
- FWCI
- 16.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32gm075583-02)
- National Institute on Aging (R37AG026647)
- National Heart, Lung, and Blood Institute (T32HL076139)
- National Institute of General Medical Sciences (T32 GM 08061, F32 GM075583-01, T32GM008061)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- polyglutamine diseases, protein folding, protein aggregation, protein quality control, temperature-sensitive mutation, genetic modifiers, neurodegenerative diseases, Caenorhabditis elegans, protein misfolding
- MeSH terms
- Animals, Disease Models, Animal, Glutamine, Humans, Mutation, Peptides, Temperature, Tropomyosin, Caenorhabditis elegans, Protein Folding, Neurodegenerative Diseases, Caenorhabditis elegans Proteins, Dynamin I
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