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ABSTRACT: Background
Accumulation of filamentous ?-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in ?-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human ?-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 ?-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing ?-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 ?-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) ?-synuclein, displayed more ?-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 ?-synuclein oligomer accumulation.Conclusions
Our results indicate that an increase of wild-type ?-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 ?-synuclein.
SUBMITTER: Jiang P
PROVIDER: S-EPMC3016345 | biostudies-literature | 2010 Dec
REPOSITORIES: biostudies-literature
Jiang Peizhou P Gan Ming M Ebrahim Abdul Shukkur AS Lin Wen-Lang WL Melrose Heather L HL Yen Shu-Hui C SH
Molecular neurodegeneration 20101213
<h4>Background</h4>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 ...[more]