دورية أكاديمية
Modulation of the maladaptive stress response to manage diseases of protein folding.
| العنوان: | Modulation of the maladaptive stress response to manage diseases of protein folding. |
|---|---|
| المؤلفون: | Daniela Martino Roth, Darren M Hutt, Jiansong Tong, Marion Bouchecareilh, Ning Wang, Theo Seeley, Johanna F Dekkers, Jeffrey M Beekman, Dan Garza, Lawrence Drew, Eliezer Masliah, Richard I Morimoto, William E Balch |
| المصدر: | PLoS Biology, Vol 12, Iss 11, p e1001998 (2014) |
| بيانات النشر: | Public Library of Science (PLoS), 2014. |
| سنة النشر: | 2014 |
| المجموعة: | LCC:Biology (General) |
| مصطلحات موضوعية: | Biology (General), QH301-705.5 |
| الوصف: | Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD), Niemann-Pick type C1 disease (NPC1), Alzheimer's disease (AD), and cystic fibrosis (CF). Using distinct models, including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans, we found that chronic expression of misfolded proteins not only triggers the sustained activation of the heat shock response (HSR) pathway, but that this sustained activation is maladaptive. In diseased cells, maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. We show that down-regulation of this maladaptive stress response (MSR), through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1544-9173 1545-7885 |
| Relation: | http://europepmc.org/articles/PMC4236052?pdf=render; https://doaj.org/toc/1544-9173; https://doaj.org/toc/1545-7885 |
| DOI: | 10.1371/journal.pbio.1001998 |
| URL الوصول: | https://doaj.org/article/a1806e3f4d0546f9a4f7421448cf23d1 |
| رقم الأكسشن: | edsdoj.1806e3f4d0546f9a4f7421448cf23d1 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 15449173 15457885 |
|---|---|
| DOI: | 10.1371/journal.pbio.1001998 |