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Human cyclophilin 40 unravels neurotoxic amyloids
The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheime...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486962/ https://www.ncbi.nlm.nih.gov/pubmed/28654636 http://dx.doi.org/10.1371/journal.pbio.2001336 |
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author | Baker, Jeremy D. Shelton, Lindsey B. Zheng, Dali Favretto, Filippo Nordhues, Bryce A. Darling, April Sullivan, Leia E. Sun, Zheying Solanki, Parth K. Martin, Mackenzie D. Suntharalingam, Amirthaa Sabbagh, Jonathan J. Becker, Stefan Mandelkow, Eckhard Uversky, Vladimir N. Zweckstetter, Markus Dickey, Chad A. Koren, John Blair, Laura J. |
author_facet | Baker, Jeremy D. Shelton, Lindsey B. Zheng, Dali Favretto, Filippo Nordhues, Bryce A. Darling, April Sullivan, Leia E. Sun, Zheying Solanki, Parth K. Martin, Mackenzie D. Suntharalingam, Amirthaa Sabbagh, Jonathan J. Becker, Stefan Mandelkow, Eckhard Uversky, Vladimir N. Zweckstetter, Markus Dickey, Chad A. Koren, John Blair, Laura J. |
author_sort | Baker, Jeremy D. |
collection | PubMed |
description | The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer’s disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids. |
format | Online Article Text |
id | pubmed-5486962 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54869622017-07-11 Human cyclophilin 40 unravels neurotoxic amyloids Baker, Jeremy D. Shelton, Lindsey B. Zheng, Dali Favretto, Filippo Nordhues, Bryce A. Darling, April Sullivan, Leia E. Sun, Zheying Solanki, Parth K. Martin, Mackenzie D. Suntharalingam, Amirthaa Sabbagh, Jonathan J. Becker, Stefan Mandelkow, Eckhard Uversky, Vladimir N. Zweckstetter, Markus Dickey, Chad A. Koren, John Blair, Laura J. PLoS Biol Research Article The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer’s disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids. Public Library of Science 2017-06-27 /pmc/articles/PMC5486962/ /pubmed/28654636 http://dx.doi.org/10.1371/journal.pbio.2001336 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Baker, Jeremy D. Shelton, Lindsey B. Zheng, Dali Favretto, Filippo Nordhues, Bryce A. Darling, April Sullivan, Leia E. Sun, Zheying Solanki, Parth K. Martin, Mackenzie D. Suntharalingam, Amirthaa Sabbagh, Jonathan J. Becker, Stefan Mandelkow, Eckhard Uversky, Vladimir N. Zweckstetter, Markus Dickey, Chad A. Koren, John Blair, Laura J. Human cyclophilin 40 unravels neurotoxic amyloids |
title | Human cyclophilin 40 unravels neurotoxic amyloids |
title_full | Human cyclophilin 40 unravels neurotoxic amyloids |
title_fullStr | Human cyclophilin 40 unravels neurotoxic amyloids |
title_full_unstemmed | Human cyclophilin 40 unravels neurotoxic amyloids |
title_short | Human cyclophilin 40 unravels neurotoxic amyloids |
title_sort | human cyclophilin 40 unravels neurotoxic amyloids |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486962/ https://www.ncbi.nlm.nih.gov/pubmed/28654636 http://dx.doi.org/10.1371/journal.pbio.2001336 |
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