Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition |
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Authors: | Yokota Takanori Sugawara Kanako Ito Kaoru Takahashi Ryosuke Ariga Hiroyoshi Mizusawa Hidehiro |
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Institution: | Department of Neurology and Neurological Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan. tak-yokota.nuro@tmd.ac.jp |
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Abstract: | Mutations in DJ-1 gene have been linked to autosomal recessive early onset parkinsonism (AR-EOP). Although the mechanism of neuronal cell death due to DJ-1 mutation has not been fully elucidated, loss of DJ-1 function was considered to cause the phenotype. Here, we demonstrated that the down regulation of endogenous DJ-1 of the neuronal cell line by siRNA enhanced the cell death which was induced by oxidative stress, ER stress, and proteasome inhibition, but not by pro-apoptotic stimulus. The cell death with hydrogen peroxide was dramatically rescued by over-expression of wild-type DJ-1, but not by that of L166P mutant DJ-1. Furthermore, DJ-1 rescued the cell death caused by over-expression of Pael receptor, which was a substrate of Parkin, another gene product for autosomal recessive juvenile parkinsonism. These results suggest that loss of protective activity of DJ-1 from neuro-toxicity induced by these stresses contributes to neuronal cell death in AR-EOP with mutant DJ-1. |
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Keywords: | DJ-1 Park 7 Autosomal recessive early onset parkinsonism Parkinson’s disease Oxidative stress Hydrogen peroxide ER stress Proteasome inhibition |
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