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Small Molecule Proteostasis Regulators for Protein Conformational Diseases

Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transc...

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Autores principales: Calamini, Barbara, Silva, Maria Catarina, Madoux, Franck, Hutt, Darren M., Khanna, Shilpi, Chalfant, Monica A., Saldanha, Sanjay A., Hodder, Peter, Tait, Bradley D., Garza, Dan, Balch, William E., Morimoto, Richard I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262058/
https://www.ncbi.nlm.nih.gov/pubmed/22198733
http://dx.doi.org/10.1038/nchembio.763
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author Calamini, Barbara
Silva, Maria Catarina
Madoux, Franck
Hutt, Darren M.
Khanna, Shilpi
Chalfant, Monica A.
Saldanha, Sanjay A.
Hodder, Peter
Tait, Bradley D.
Garza, Dan
Balch, William E.
Morimoto, Richard I.
author_facet Calamini, Barbara
Silva, Maria Catarina
Madoux, Franck
Hutt, Darren M.
Khanna, Shilpi
Chalfant, Monica A.
Saldanha, Sanjay A.
Hodder, Peter
Tait, Bradley D.
Garza, Dan
Balch, William E.
Morimoto, Richard I.
author_sort Calamini, Barbara
collection PubMed
description Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting a promising therapeutic approach. We describe the results of a ∼900,000 small molecule screen that identified novel classes of small molecule proteostasis regulators (PRs) that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. The beneficial effects to proteome stability are mediated by HSF-1, DAF-16/FOXO, SKN-1/Nrf-2, and the chaperone machinery through mechanisms that are distinct from current known small molecule activators of the HSR. We suggest that modulation of the proteostasis network by PRs represents a promising therapeutic approach for the treatment of a variety of protein conformational diseases.
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spelling pubmed-32620582012-08-01 Small Molecule Proteostasis Regulators for Protein Conformational Diseases Calamini, Barbara Silva, Maria Catarina Madoux, Franck Hutt, Darren M. Khanna, Shilpi Chalfant, Monica A. Saldanha, Sanjay A. Hodder, Peter Tait, Bradley D. Garza, Dan Balch, William E. Morimoto, Richard I. Nat Chem Biol Article Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting a promising therapeutic approach. We describe the results of a ∼900,000 small molecule screen that identified novel classes of small molecule proteostasis regulators (PRs) that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. The beneficial effects to proteome stability are mediated by HSF-1, DAF-16/FOXO, SKN-1/Nrf-2, and the chaperone machinery through mechanisms that are distinct from current known small molecule activators of the HSR. We suggest that modulation of the proteostasis network by PRs represents a promising therapeutic approach for the treatment of a variety of protein conformational diseases. 2011-12-25 /pmc/articles/PMC3262058/ /pubmed/22198733 http://dx.doi.org/10.1038/nchembio.763 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Calamini, Barbara
Silva, Maria Catarina
Madoux, Franck
Hutt, Darren M.
Khanna, Shilpi
Chalfant, Monica A.
Saldanha, Sanjay A.
Hodder, Peter
Tait, Bradley D.
Garza, Dan
Balch, William E.
Morimoto, Richard I.
Small Molecule Proteostasis Regulators for Protein Conformational Diseases
title Small Molecule Proteostasis Regulators for Protein Conformational Diseases
title_full Small Molecule Proteostasis Regulators for Protein Conformational Diseases
title_fullStr Small Molecule Proteostasis Regulators for Protein Conformational Diseases
title_full_unstemmed Small Molecule Proteostasis Regulators for Protein Conformational Diseases
title_short Small Molecule Proteostasis Regulators for Protein Conformational Diseases
title_sort small molecule proteostasis regulators for protein conformational diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262058/
https://www.ncbi.nlm.nih.gov/pubmed/22198733
http://dx.doi.org/10.1038/nchembio.763
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