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Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor

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Abstract

At the neuropathological level, Parkinson’s disease (PD) is characterized by the accumulation of misfolded proteins, which can trigger the unfolded protein response (UPR). UCH-L1 is a component of ubiquitin proteasome system (UPS). It is reported that the loss of its function will impair ubiquitin proteasome system and cause toxicity to cells. But its mechanism has not been illustrated. In this study, we detected the protein expression of Bip/Grp78 and the spliced form of XBP-1 to examine the activation of unfolded protein response after SK-N-SH cells being treated with LDN-57444, a UCH-L1 inhibitor which could inhibit UCH-L1 hydrolase activity. Our data showed that UCH-L1 inhibitor was able to cause cell death through the apoptosis pathway by decreasing the activity of ubiquitin proteasome system and increasing the levels of highly ubiquitinated proteins, both of which can activate unfolded protein response. There is a lot of evidence that unfolded protein response is activated as a protective response at the early stage of the stress; this protective response can switch to a pro-apoptotic response when the stress persists. In this study, we demonstrated this switch by detecting the upregulation of CHOP/Gadd153. Taken together, our data indicated that the apoptosis induced by UCH-L1 inhibitor may be triggered by the activation of endoplasmic reticulum stress (ERS). Moreover, we provide a new cell model for studying the roles of UCH-L1 in Parkinson’s disease.

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Acknowledgments

This work was supported by grants from the National Program of Basic Research (2006CB500706) of China, National Natural Science Fund (30471918, 30570637), Shanghai Key Project of Basic Science Research (04DZ14005) and Program for Outstanding Medical Academic Leader (LJ 06003).

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Authors and Affiliations

  1. Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Yu-Yan Tan, Hai-Yan Zhou & Sheng-Di Chen

  2. Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Yu-Yan Tan, Zhi-Quan Wang & Sheng-Di Chen

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  1. Yu-Yan Tan
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Correspondence to Sheng-Di Chen.

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Tan, YY., Zhou, HY., Wang, ZQ. et al. Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor. Mol Cell Biochem 318, 109–115 (2008). https://doi.org/10.1007/s11010-008-9862-x

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  • DOI: https://doi.org/10.1007/s11010-008-9862-x

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