Inhibition of synucleinopathic seeding by rationally designed inhibitors
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Seeding, in the context of amyloid disease, is the sequential transfer of pathogenic protein aggregates from cell-to-cell within affected tissues. The structure of pathogenic seeds provides the molecular basis and enables rapid conversion of soluble protein into fibrils. To date, there are no inhibitors that specifically target seeding of Parkinson’s disease (PD)-associated α-synuclein (α-syn) fibrils, in part, due to lack of information of the structural properties of pathological seeds. Here we design small peptidic inhibitors based on the atomic structure of the core of α-syn fibrils. The inhibitors prevent α-syn aggregation in vitro and in cell culture models with binding affinities of 0.5 μM to α-syn fibril seeds. The inhibitors also show efficacy in preventing seeding by human patient-derived α-syn fibrils. Our results suggest that pathogenic seeds of α-syn contain steric zippers and suggest a therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.
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Short peptides with altered amino acid sequences that target cross-sectional interfaces have been successfully employed in capping of various amyloid fibrils and inhibition of seeding.
“Notably, short peptides with altered amino acid sequences that target the cross-sectional interfaces of aggregation-prone regions have been successfully employed in the capping of various amyloid fibrils and the inhibition of seeding (63, 64, 65, 66).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [66]
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- Authors
- Sangwan, S., Sahay, S., Murray, K. A., Morgan, S., Guenther, E. L., Jiang, L., Williams, C. K., Vinters, H. V., Goedert, M., & Eisenberg, D. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- MRC Laboratory of Molecular Biology (GB)
- University of California, Los Angeles (US)
- Corresponding author
- Eisenberg, David S
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-01-02
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6977966
- OpenAlex
- W2998292457
- Cited by
- 79
- References
- 35
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 8 · 2023: 14 · 2022: 11 · 2021: 13 · 2020: 8
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (AG054022, R01AG060149)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, seeding, synucleinopathies, Parkinson's disease, peptide inhibitors, protein aggregation, steric zipper, amyloidosis, rational inhibitor design, cell-to-cell transmission
- MeSH terms
- Humans, Parkinson Disease, alpha-Synuclein, HEK293 Cells, Protein Aggregation, Pathological, Protein Aggregates
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