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The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease

The wild type huntingtin protein (Htt), supports the production of brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, through cytoplasmic sequestering of RE-1silencing transcription factor (REST). In Huntington´s Disease an inherited degenerative disease, caused by a C...

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Autores principales: Orozco-Díaz, Raúl, Sánchez-Álvarez, Angélica, Hernández-Hernández, José Manuel, Tapia-Ramírez, José
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667143/
https://www.ncbi.nlm.nih.gov/pubmed/31361762
http://dx.doi.org/10.1371/journal.pone.0220393
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author Orozco-Díaz, Raúl
Sánchez-Álvarez, Angélica
Hernández-Hernández, José Manuel
Tapia-Ramírez, José
author_facet Orozco-Díaz, Raúl
Sánchez-Álvarez, Angélica
Hernández-Hernández, José Manuel
Tapia-Ramírez, José
author_sort Orozco-Díaz, Raúl
collection PubMed
description The wild type huntingtin protein (Htt), supports the production of brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, through cytoplasmic sequestering of RE-1silencing transcription factor (REST). In Huntington´s Disease an inherited degenerative disease, caused by a CAG expansion in the 5´coding region of the gene, the mutant huntingtin protein (mHtt), causes that REST enters pathologically into the nucleus of cells, resulting in the repression of neuronal genes including BDNF, resulting in the progressive neuronal death. It has been reported that Htt associates with Hsp90 and this interaction is involved in regulation of huntingtin aggregation. Discovering mechanisms to reduce the cellular levels of mutant huntingtin and REST provide promising strategies for treating Huntington disease. Here, we use the yeast two-hybrid system to show that N-terminus or REST interacts with the heat shock protein 90 (Hsp90) and identifies REST as an Hsp90 Client Protein. To assess the effects of Hsp90 we used antisense oligonucleotide, and evaluated the levels mHtt and REST levels. Our results show that direct knockdown of endogenous Hsp90 significantly reduces the levels of REST and mutant Huntingtin, decreased the percentage of cells with mHtt in nucleus and rescued cells from mHtt-induced cellular cytotoxicity. Additionally Hsp90–specific inhibitors geldanamicyn and PUH71 dramatically reduced mHtt and REST levels, thereby providing neuroprotective activity. Our data show that Hsp90 is necessary to maintain the levels of REST and mHtt, which suggests that the interactions between Hsp90-REST and Hsp90-Huntingtin could be potential therapeutic targets in Huntington's disease.
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spelling pubmed-66671432019-08-07 The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease Orozco-Díaz, Raúl Sánchez-Álvarez, Angélica Hernández-Hernández, José Manuel Tapia-Ramírez, José PLoS One Research Article The wild type huntingtin protein (Htt), supports the production of brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, through cytoplasmic sequestering of RE-1silencing transcription factor (REST). In Huntington´s Disease an inherited degenerative disease, caused by a CAG expansion in the 5´coding region of the gene, the mutant huntingtin protein (mHtt), causes that REST enters pathologically into the nucleus of cells, resulting in the repression of neuronal genes including BDNF, resulting in the progressive neuronal death. It has been reported that Htt associates with Hsp90 and this interaction is involved in regulation of huntingtin aggregation. Discovering mechanisms to reduce the cellular levels of mutant huntingtin and REST provide promising strategies for treating Huntington disease. Here, we use the yeast two-hybrid system to show that N-terminus or REST interacts with the heat shock protein 90 (Hsp90) and identifies REST as an Hsp90 Client Protein. To assess the effects of Hsp90 we used antisense oligonucleotide, and evaluated the levels mHtt and REST levels. Our results show that direct knockdown of endogenous Hsp90 significantly reduces the levels of REST and mutant Huntingtin, decreased the percentage of cells with mHtt in nucleus and rescued cells from mHtt-induced cellular cytotoxicity. Additionally Hsp90–specific inhibitors geldanamicyn and PUH71 dramatically reduced mHtt and REST levels, thereby providing neuroprotective activity. Our data show that Hsp90 is necessary to maintain the levels of REST and mHtt, which suggests that the interactions between Hsp90-REST and Hsp90-Huntingtin could be potential therapeutic targets in Huntington's disease. Public Library of Science 2019-07-30 /pmc/articles/PMC6667143/ /pubmed/31361762 http://dx.doi.org/10.1371/journal.pone.0220393 Text en © 2019 Orozco-Díaz et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Orozco-Díaz, Raúl
Sánchez-Álvarez, Angélica
Hernández-Hernández, José Manuel
Tapia-Ramírez, José
The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
title The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
title_full The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
title_fullStr The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
title_full_unstemmed The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
title_short The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
title_sort interaction between re1-silencing transcription factor (rest) and heat shock protein 90 as new therapeutic target against huntington’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667143/
https://www.ncbi.nlm.nih.gov/pubmed/31361762
http://dx.doi.org/10.1371/journal.pone.0220393
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