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Staufen 1 amplifies proapoptotic activation of the unfolded protein response
Staufen-1 (STAU1) is an RNA-binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule-associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP), or C9orf72. We...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492261/ https://www.ncbi.nlm.nih.gov/pubmed/32415281 http://dx.doi.org/10.1038/s41418-020-0553-9 |
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author | Gandelman, Mandi Dansithong, Warunee Figueroa, Karla P. Paul, Sharan Scoles, Daniel R. Pulst, Stefan M. |
author_facet | Gandelman, Mandi Dansithong, Warunee Figueroa, Karla P. Paul, Sharan Scoles, Daniel R. Pulst, Stefan M. |
author_sort | Gandelman, Mandi |
collection | PubMed |
description | Staufen-1 (STAU1) is an RNA-binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule-associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP), or C9orf72. We previously reported that elevations in STAU1 determine autophagy defects and its knockdown is protective in models of several neurodegenerative diseases. Additional functional consequences of STAU1 overabundance, however, have not been investigated. We studied the role of STAU1 in the chronic activation of the unfolded protein response (UPR), a common feature among neurodegenerative diseases and often directly associated with neuronal death. Here we report that STAU1 is a novel modulator of the UPR, and is required for apoptosis induced by activation of the PERK–CHOP pathway. STAU1 levels increased in response to multiple endoplasmic reticulum (ER) stressors, and exogenous expression of STAU1 was sufficient to cause apoptosis through the PERK–CHOP pathway of the UPR. Cortical neurons and skin fibroblasts derived from Stau1(−/−) mice showed reduced UPR and apoptosis when challenged with thapsigargin. In fibroblasts from individuals with SCA2 or with ALS-causing TDP-43 and C9ORF72 mutations, we found highly increased STAU1 and CHOP levels in basal conditions, and STAU1 knockdown restored CHOP levels to normal. Taken together, these results show that STAU1 overabundance reduces cellular resistance to ER stress and precipitates apoptosis. |
format | Online Article Text |
id | pubmed-7492261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74922612020-10-01 Staufen 1 amplifies proapoptotic activation of the unfolded protein response Gandelman, Mandi Dansithong, Warunee Figueroa, Karla P. Paul, Sharan Scoles, Daniel R. Pulst, Stefan M. Cell Death Differ Article Staufen-1 (STAU1) is an RNA-binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule-associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP), or C9orf72. We previously reported that elevations in STAU1 determine autophagy defects and its knockdown is protective in models of several neurodegenerative diseases. Additional functional consequences of STAU1 overabundance, however, have not been investigated. We studied the role of STAU1 in the chronic activation of the unfolded protein response (UPR), a common feature among neurodegenerative diseases and often directly associated with neuronal death. Here we report that STAU1 is a novel modulator of the UPR, and is required for apoptosis induced by activation of the PERK–CHOP pathway. STAU1 levels increased in response to multiple endoplasmic reticulum (ER) stressors, and exogenous expression of STAU1 was sufficient to cause apoptosis through the PERK–CHOP pathway of the UPR. Cortical neurons and skin fibroblasts derived from Stau1(−/−) mice showed reduced UPR and apoptosis when challenged with thapsigargin. In fibroblasts from individuals with SCA2 or with ALS-causing TDP-43 and C9ORF72 mutations, we found highly increased STAU1 and CHOP levels in basal conditions, and STAU1 knockdown restored CHOP levels to normal. Taken together, these results show that STAU1 overabundance reduces cellular resistance to ER stress and precipitates apoptosis. Nature Publishing Group UK 2020-05-15 2020-10 /pmc/articles/PMC7492261/ /pubmed/32415281 http://dx.doi.org/10.1038/s41418-020-0553-9 Text en © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020, corrected publication 2021 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/. |
spellingShingle | Article Gandelman, Mandi Dansithong, Warunee Figueroa, Karla P. Paul, Sharan Scoles, Daniel R. Pulst, Stefan M. Staufen 1 amplifies proapoptotic activation of the unfolded protein response |
title | Staufen 1 amplifies proapoptotic activation of the unfolded protein response |
title_full | Staufen 1 amplifies proapoptotic activation of the unfolded protein response |
title_fullStr | Staufen 1 amplifies proapoptotic activation of the unfolded protein response |
title_full_unstemmed | Staufen 1 amplifies proapoptotic activation of the unfolded protein response |
title_short | Staufen 1 amplifies proapoptotic activation of the unfolded protein response |
title_sort | staufen 1 amplifies proapoptotic activation of the unfolded protein response |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492261/ https://www.ncbi.nlm.nih.gov/pubmed/32415281 http://dx.doi.org/10.1038/s41418-020-0553-9 |
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