Inhibition of synucleinopathic seeding by rationally designed inhibitors
- Howard Hughes Medical Institute, University of California, Los Angeles, United States
- MRC Laboratory of Molecular Biology, United Kingdom
- University of California, Los Angeles, United States
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript. A source data file has been provided for Figures 2,3,4,5 and 7.
Article and author information
Author details
Funding
National Institutes of Health (AG054022)
- David S Eisenberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael B Eisen, HHMI, University of California, Berkeley, United States
Version history
- Received: March 12, 2019
- Accepted: November 13, 2019
- Accepted Manuscript published: January 2, 2020 (version 1)
- Version of Record published: January 23, 2020 (version 2)
Copyright
© 2020, Sangwan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibition of synucleinopathic seeding by rationally designed inhibitors
eLife 9:e46775.
https://doi.org/10.7554/eLife.46775
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