Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases
Abstract
A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3'-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.
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Numerous mechanistic parallels have been recognized between AD and other neurodegenerative disorders, including similar protein aggregate pathologies, proteostatic and oxidative stress, neuroinflammation, and critical role of aging.
“Numerous mechanistic parallels have been recognized between AD and other neurodegenerative disorders, including similar protein aggregate pathologies, proteostatic and oxidative stress, neuroinflammation, and the critical role of aging in disease risk and/or progression (Block and Hong, 2005; Bucciantini et al., 2002; Guo and Lee, 2014; Haass and Selkoe, 2007; Nixon, 2005; Ross and Poirier, 2004).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Bucciantini et al., 2002
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“The “Amyloid Hypothesis” assumes a central role for Aβ in the pathogenesis of AD and characterizes AD as a “protein misfolding disease” which leads to aggregation and toxic accumulation of Aβ in the brain (17, 18).”
Background
- Authors
- Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C. M., & Stefani, M.
- Affiliations
- University of Florence (IT)
- University of Cambridge (GB)
- Corresponding author
- Dobson, Christopher M.
- Stefani, Massimo
- ORCID
- Venue
- Nature
- Published
- 2002-04
- Volume
- 416
- Issue
- 6880
- Pages
- 507-511
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2093861673
- Cited by
- 2,434
- References
- 4
- Citations by year
- 2026: 17 · 2025: 34 · 2024: 44 · 2023: 45 · 2022: 53 · 2021: 76 · 2020: 99 · 2019: 85 · 2018: 96 · 2017: 92 · 2016: 86 · 2015: 105 · 2014: 118 · 2013: 138 · 2012: 149
- FWCI
- 50.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Funders
- Wellcome Trust
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Keywords
- proteinopathies, protein aggregation, amyloid fibrils, cytotoxicity, Alzheimer's disease, AL amyloidosis, spongiform encephalopathy, SH3 domain, phosphatidylinositol 3-kinase, Escherichia coli, amyloidosis, protein aggregation prevention
- MeSH terms
- Alzheimer Disease, Animals, Bacterial Proteins, Cytotoxins, Biological Evolution, Humans, Recombinant Proteins, 3T3 Cells, PC12 Cells, Protein Folding, src Homology Domains, Neurodegenerative Diseases, Phosphatidylinositol 3-Kinases, Mice, Rats, Plaque, Amyloid
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