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Inhibition of synucleinopathic seeding by rationally designed inhibitors

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 inhibi...

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Autores principales: Sangwan, Smriti, Sahay, Shruti, Murray, Kevin A, Morgan, Sophie, Guenther, Elizabeth L, Jiang, Lin, Williams, Christopher K, Vinters, Harry V, Goedert, Michel, Eisenberg, David S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977966/
https://www.ncbi.nlm.nih.gov/pubmed/31895037
http://dx.doi.org/10.7554/eLife.46775
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author Sangwan, Smriti
Sahay, Shruti
Murray, Kevin A
Morgan, Sophie
Guenther, Elizabeth L
Jiang, Lin
Williams, Christopher K
Vinters, Harry V
Goedert, Michel
Eisenberg, David S
author_facet Sangwan, Smriti
Sahay, Shruti
Murray, Kevin A
Morgan, Sophie
Guenther, Elizabeth L
Jiang, Lin
Williams, Christopher K
Vinters, Harry V
Goedert, Michel
Eisenberg, David S
author_sort Sangwan, Smriti
collection PubMed
description 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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spelling pubmed-69779662020-01-27 Inhibition of synucleinopathic seeding by rationally designed inhibitors Sangwan, Smriti Sahay, Shruti Murray, Kevin A Morgan, Sophie Guenther, Elizabeth L Jiang, Lin Williams, Christopher K Vinters, Harry V Goedert, Michel Eisenberg, David S eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2020-01-02 /pmc/articles/PMC6977966/ /pubmed/31895037 http://dx.doi.org/10.7554/eLife.46775 Text en © 2020, Sangwan et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Sangwan, Smriti
Sahay, Shruti
Murray, Kevin A
Morgan, Sophie
Guenther, Elizabeth L
Jiang, Lin
Williams, Christopher K
Vinters, Harry V
Goedert, Michel
Eisenberg, David S
Inhibition of synucleinopathic seeding by rationally designed inhibitors
title Inhibition of synucleinopathic seeding by rationally designed inhibitors
title_full Inhibition of synucleinopathic seeding by rationally designed inhibitors
title_fullStr Inhibition of synucleinopathic seeding by rationally designed inhibitors
title_full_unstemmed Inhibition of synucleinopathic seeding by rationally designed inhibitors
title_short Inhibition of synucleinopathic seeding by rationally designed inhibitors
title_sort inhibition of synucleinopathic seeding by rationally designed inhibitors
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977966/
https://www.ncbi.nlm.nih.gov/pubmed/31895037
http://dx.doi.org/10.7554/eLife.46775
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