title: ER stress response plays an important role in aggregation of α-synuclein.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. Yen.shu-hui@mayo.edu.
authors.forename: Peizhou
authors.initials: P
authors.lastname: Jiang
authors.forename: Ming
authors.initials: M
authors.lastname: Gan
authors.forename: Abdul Shukkur
authors.initials: AS
authors.lastname: Ebrahim
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Heather L
authors.initials: HL
authors.lastname: Melrose
authors.forename: Shu-Hui C
authors.initials: SH
authors.lastname: Yen