Inhibition of synucleinopathic seeding by rationally designed inhibitors

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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.

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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.

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Smriti Sangwan

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Shruti Sahay

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Kevin A Murray

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Sophie Morgan

MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Elizabeth L Guenther

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Lin Jiang

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Christopher K Williams

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Harry V Vinters

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Michel Goedert

MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Competing interests
Michel Goedert, Reviewing editor, eLife.
David S Eisenberg

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

For correspondence
david@mbi.ucla.edu

Competing interests
David S Eisenberg, SAB member and equity holder in ADRx, Inc.

"This ORCID iD identifies the author of this article:" 0000-0003-2432-5419

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.

Copyright

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.