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

Peizhou Jiang, Ming Gan, Abdul Shukkur Ebrahim, Wen Lang Lin, Heather L Melrose, Shu Hui C Yen

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number56
JournalMolecular Neurodegeneration
Volume5
Issue number1
DOIs
StatePublished - 2010

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Synucleins
Primary Cell Culture
Lewy Bodies
Pharmaceutical Preparations
Tunicamycin
Histone Deacetylase Inhibitors
Caspase Inhibitors
Caspase 9
Caspase 3
Transgenic Mice
Parkinson Disease

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

ER stress response plays an important role in aggregation of -synuclein. / Jiang, Peizhou; Gan, Ming; Ebrahim, Abdul Shukkur; Lin, Wen Lang; Melrose, Heather L; Yen, Shu Hui C.

In: Molecular Neurodegeneration, Vol. 5, No. 1, 56, 2010.

Research output: Contribution to journalArticle

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 -synuclein. In: Molecular Neurodegeneration. 2010 ; Vol. 5, No. 1.
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