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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-6977966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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