ArticleThe EMBO journal2025
Structural polymorphism of α-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation.
Article in The EMBO journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- From aggregate structure to disease trajectory: the role of the proteostasis network.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Small bites for big problems: stepwise aggregate degradation by autophagy.Biochemical Society transactions · 2026Review
- Amyloid fibril polymorphism: Structural mechanisms of assembly and the links to disease.Current opinion in structural biology · 2026Review
- Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.Molecular systems biology · 2026Article
- Thermodynamic stability modulates chaperone-mediated disaggregation of α-synuclein fibrils.Chemical science · 2026Article
- AI-Guided Dual Strategy for Peptide Inhibitor Design Targeting Structural Polymorphs of α-Synuclein Fibrils.Cells · 2025Article
- How Sup35 monomer conformation and amyloid fibril polymorphism determine yeast strain phenotypes.Research square · 2025Article
- DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.bioRxiv : the preprint server for biology · 2025Article
- Competing chaperone pathways in α-synuclein disaggregation and aggregation dynamics.Protein science : a publication of the Protein Society · 2025Article
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Authors and funding
11 authors.
Funding
Abstract
Pathological aggregation of α-synuclein into amyloid fibrils is a hallmark of synucleinopathies, including Parkinson's disease. Despite this commonality, synucleinopathies display divergent disease phenotypes that have been attributed to disease-specific three-dimensional structures of α-synuclein fibrils, each with unique toxic gain-of-function profiles. The Hsc70 chaperone is remarkable in its ability to disassemble pre-existing amyloid fibrils of different proteins in an ATP and co-chaperone-dependent manner. We find, however, using six well-defined conformational polymorphs of α-synuclein fibrils, that the activity of the Hsc70 disaggregase machinery is sensitive to differences in the amyloid conformation, confirming that fibril polymorphism directly affects interactions with the proteostasis network. Amyloid conformation influences not only how efficiently fibrils are cleared by the Hsc70 machinery but also the balance between depolymerization and fragmentation during disaggregation. We further show that, in vitro, the active processing of fibrils by the Hsc70 machinery inadvertently produces seeding competent species that further promote protein aggregation. Amyloid conformation thus is an important feature that can tilt the balance between beneficial or detrimental protein quality control activities in a disease-context.
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