Endogenous catecholamine enhances the dysfunction of unfolded protein response and α-synuclein oligomerization in PC12 cells overexpressing human α-synuclein
Endogenous catecholamine enhances the dysfunction of unfolded protein response and α-synuclein oligomerization in PC12 cells overexpressing human α-synuclein
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DOI：
10.1016/j.neures.2009.10.005
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发表时间：
2010-01-01
影响因子：
2.9
通讯作者：
Nakashima, Kenji
中科院分区：
文献类型：
--
作者：
Ito, Satoru;Nakaso, Kazuhiro;Nakashima, Kenji
帕金森病（PD）是一种神经退行性疾病，其特征是多巴胺能神经元的选择性丧失和路易体的存在。 α-突触核蛋白是路易体的主要成分。最近，许多研究集中在帕金森病发病机制中α-突触核蛋白和儿茶酚胺之间的相互作用。然而，尚未阐明儿茶酚胺和α-突触核蛋白细胞毒性之间的详细关系。因此，本研究建立了以四环素诱导方式过表达人α-突触核蛋白的PC12细胞系。人α-突触核蛋白的过度表达增加了长期培养中凋亡细胞的数量。此外，表达人类α-突触核蛋白的PC12细胞在短期培养期间表现出对多种应激源的脆弱性增加。毒胡萝卜素增加了与儿茶酚胺醌相关的 α-突触核蛋白的 SIDS 可溶性低聚物。未折叠蛋白反应 (UPR) 研究表明，在 α-突触核蛋白过表达条件下，毒胡萝卜素可增加 eIF2 α 磷酸化和核 GADD153/CHOP 诱导。 ATF6 α 和 IRE1 α 通路的活性降低。这些发现表明，α-突触核蛋白的过度表达会部分地使 UPR 失活。 α-甲基酪氨酸抑制由人α-突触核蛋白过度表达引起的 UPR 功能障碍。因此，这些研究结果表明，人α-突触核蛋白与儿茶酚胺的共存增强了PD发病机制中内质网应激相关的毒性。 (C) 2009 Elsevier Ireland Ltd 和日本神经科学学会。版权所有。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies. Recently, many studies have focused on the interaction between alpha-synuclein and catecholamine in the pathogenesis of PD. However, no detailed relationship between cathecholamine and alpha-synuclein cytotoxicity has been elucidated. Therefore, this study established PC12 cell lines which overexpress human alpha-synuclein in a tetracycline-inducible manner. The overexpression of human alpha-synuclein increased the number of apoptotic cells in a long-term culture. Moreover, human alpha-synuclein expressing PC12 cells demonstrated an increased vulnerability to several stressors in a short culture period. Thapsigargin increased the SIDS soluble oligomers of alpha-synuclein associated with catecholamine-quinone. The unfolded protein response (UPR) study showed that thapsigargin increased eIF2 alpha phosphorylation and nuclear GADD153/CHOP induction under alpha-synuclein overexpressed conditions. The activities of the ATF6 alpha and IRE1 alpha pathways decreased. These findings suggest that an overexpression of alpha-synuclein partly inactivates the UPR. alpha-Methyltyrosine inhibited the dysfunction of the UPR caused by an overexpression of human alpha-synuclein. Therefore, these findings suggest that the coexistence of human alpha-synuclein with catecholamine enhances the endoplasmic reticulum stress-related toxicity in PD pathogenesis. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.