1. Biochemistry and Chemical Biology
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Inhibition of synucleinopathic seeding by rationally designed inhibitors

  1. Smriti Sangwan
  2. Shruti Sahay
  3. Kevin A Murray
  4. Sophie Morgan
  5. Elizabeth L Guenther
  6. Lin Jiang
  7. Christopher K Williams
  8. Harry V Vinters
  9. Michel Goedert
  10. David S Eisenberg  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Los Angeles, United States
  2. MRC Laboratory of Molecular Biology, United Kingdom
  3. University of California, Los Angeles, United States
Research Article
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Cite this article as: eLife 2020;9:e46775 doi: 10.7554/eLife.46775

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

  1. Smriti Sangwan

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  2. Shruti Sahay

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  3. Kevin A Murray

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Sophie Morgan

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  5. Elizabeth L Guenther

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  6. 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.
  7. Christopher K Williams

    Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  8. Harry V Vinters

    Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  9. Michel Goedert

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    Michel Goedert, Reviewing editor, eLife.
  10. 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.
    ORCID icon "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.

Reviewing Editor

  1. Michael B Eisen, HHMI, University of California, Berkeley, United States

Publication history

  1. Received: March 12, 2019
  2. Accepted: November 13, 2019
  3. Accepted Manuscript published: January 2, 2020 (version 1)
  4. 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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