ER stress response plays an important role in aggregation of α-synuclein

Background: Accumulation of filamentous alpha-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in alpha-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human alpha-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 a alpha-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing alpha-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 alpha-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) alpha-synuclein, displayed more alpha-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 alpha-synuclein oligomer accumulation. Conclusions: Our results indicate that an increase of wild-type alpha-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 alpha-synuclein.