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ER stress response plays an important role in aggregation of α-synuclein
BACKGROUND: Accumulation of filamentous α-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in α-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human α-syn...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016345/ https://www.ncbi.nlm.nih.gov/pubmed/21144044 http://dx.doi.org/10.1186/1750-1326-5-56 |
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author | Jiang, Peizhou Gan, Ming Ebrahim, Abdul Shukkur Lin, Wen-Lang Melrose, Heather L Yen, Shu-Hui C |
author_facet | Jiang, Peizhou Gan, Ming Ebrahim, Abdul Shukkur Lin, Wen-Lang Melrose, Heather L Yen, Shu-Hui C |
author_sort | Jiang, Peizhou |
collection | PubMed |
description | BACKGROUND: Accumulation of filamentous α-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in α-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human α-synuclein and forms inclusions that reproduce many morphological and biochemical characteristics of Lewy bodies. In the present study, we evaluated the effects of several histone deacetylase inhibitors on α-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing α-synuclein from its toxicity. RESULTS: Contrary to transient transfectants, the drug treatment did not benefit 3D5 cells and primary cultures. The treated were less viable and contained more α-synuclein oligomers, active caspases 3 and 9, as well as ER stress markers than non-treated counterparts. The drug-treated, induced-3D5 cells, or primary cultures from transgenic mice overexpressing (<2 fold) α-synuclein, displayed more α-synuclein oligomers and ER stress markers than non-induced or non-transgenic counterparts. Similar effects were demonstrated in cultures treated with tunicamycin, an ER stressor. These effects were blocked by co-treatment with salubrinal, an ER stress inhibitor. In comparison, co-treatment with a pan caspase inhibitor protected cells from demise but did not reduce α-synuclein oligomer accumulation. CONCLUSIONS: Our results indicate that an increase of wild-type α-synuclein can elicit ER stress response and sensitize cells to further insults. Most importantly, an increase of ER stress response can promote the aggregation of wild type α-synuclein. |
format | Text |
id | pubmed-3016345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-30163452011-01-06 ER stress response plays an important role in aggregation of α-synuclein Jiang, Peizhou Gan, Ming Ebrahim, Abdul Shukkur Lin, Wen-Lang Melrose, Heather L Yen, Shu-Hui C Mol Neurodegener Research Article BACKGROUND: Accumulation of filamentous α-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in α-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human α-synuclein and forms inclusions that reproduce many morphological and biochemical characteristics of Lewy bodies. In the present study, we evaluated the effects of several histone deacetylase inhibitors on α-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing α-synuclein from its toxicity. RESULTS: Contrary to transient transfectants, the drug treatment did not benefit 3D5 cells and primary cultures. The treated were less viable and contained more α-synuclein oligomers, active caspases 3 and 9, as well as ER stress markers than non-treated counterparts. The drug-treated, induced-3D5 cells, or primary cultures from transgenic mice overexpressing (<2 fold) α-synuclein, displayed more α-synuclein oligomers and ER stress markers than non-induced or non-transgenic counterparts. Similar effects were demonstrated in cultures treated with tunicamycin, an ER stressor. These effects were blocked by co-treatment with salubrinal, an ER stress inhibitor. In comparison, co-treatment with a pan caspase inhibitor protected cells from demise but did not reduce α-synuclein oligomer accumulation. CONCLUSIONS: Our results indicate that an increase of wild-type α-synuclein can elicit ER stress response and sensitize cells to further insults. Most importantly, an increase of ER stress response can promote the aggregation of wild type α-synuclein. BioMed Central 2010-12-13 /pmc/articles/PMC3016345/ /pubmed/21144044 http://dx.doi.org/10.1186/1750-1326-5-56 Text en Copyright ©2010 Jiang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Jiang, Peizhou Gan, Ming Ebrahim, Abdul Shukkur Lin, Wen-Lang Melrose, Heather L Yen, Shu-Hui C ER stress response plays an important role in aggregation of α-synuclein |
title | ER stress response plays an important role in aggregation of α-synuclein |
title_full | ER stress response plays an important role in aggregation of α-synuclein |
title_fullStr | ER stress response plays an important role in aggregation of α-synuclein |
title_full_unstemmed | ER stress response plays an important role in aggregation of α-synuclein |
title_short | ER stress response plays an important role in aggregation of α-synuclein |
title_sort | er stress response plays an important role in aggregation of α-synuclein |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016345/ https://www.ncbi.nlm.nih.gov/pubmed/21144044 http://dx.doi.org/10.1186/1750-1326-5-56 |
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