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Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansio...

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Autores principales: Babu, Maria, Favretto, Filippo, de Opakua, Alain Ibáñez, Rankovic, Marija, Becker, Stefan, Zweckstetter, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184751/
https://www.ncbi.nlm.nih.gov/pubmed/34099711
http://dx.doi.org/10.1038/s41467-021-23691-y
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author Babu, Maria
Favretto, Filippo
de Opakua, Alain Ibáñez
Rankovic, Marija
Becker, Stefan
Zweckstetter, Markus
author_facet Babu, Maria
Favretto, Filippo
de Opakua, Alain Ibáñez
Rankovic, Marija
Becker, Stefan
Zweckstetter, Markus
author_sort Babu, Maria
collection PubMed
description Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.
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spelling pubmed-81847512021-06-09 Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis Babu, Maria Favretto, Filippo de Opakua, Alain Ibáñez Rankovic, Marija Becker, Stefan Zweckstetter, Markus Nat Commun Article Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases. Nature Publishing Group UK 2021-06-07 /pmc/articles/PMC8184751/ /pubmed/34099711 http://dx.doi.org/10.1038/s41467-021-23691-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Babu, Maria
Favretto, Filippo
de Opakua, Alain Ibáñez
Rankovic, Marija
Becker, Stefan
Zweckstetter, Markus
Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
title Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
title_full Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
title_fullStr Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
title_full_unstemmed Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
title_short Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
title_sort proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184751/
https://www.ncbi.nlm.nih.gov/pubmed/34099711
http://dx.doi.org/10.1038/s41467-021-23691-y
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