Parkin attenuates manganese-induced dopaminergic cell death
Parkin attenuates manganese-induced dopaminergic cell death
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DOI：
10.1111/j.1471-4159.2004.02445.x
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发表时间：
2004-06-01
影响因子：
4.7
通讯作者：
Ogawa, N
中科院分区：
文献类型：
--
作者：
Higashi, Y;Asanuma, M;Ogawa, N
锰作为环境因素被认为是导致帕金森病和诱导内质网应激介导的多巴胺能细胞死亡的因素。我们研究了锰对parkin的影响，parkin被认为是导致家族性帕金森病的基因，以及parkin在锰诱导的神经细胞死亡中的作用。锰可剂量依赖性地诱导多巴胺能SH-SY5Y和CATH.a细胞及胆碱能神经-2a细胞死亡，且前两种细胞对锰的毒性比神经-2a细胞更敏感。此外，在SH-SY5Y细胞和CATH.a细胞中，锰增加了内质网应激相关基因的表达，包括parkin，但在Neuro-2a细胞中没有。经锰处理后，Parkin蛋白在SH-SY5Y细胞中积聚，并重新分布到核周区域，尤其是聚集的高尔基复合体，而在Neuro-2a细胞中没有观察到Parkin蛋白的表达和再分布。锰对两种细胞中的蛋白酶体活性均无影响。瞬时转染parkin基因可抑制锰或锰加多巴胺诱导的SH-SY5Y细胞死亡，但不能抑制Neuro-2a细胞的死亡。我们的结果表明，parkin对锰或锰加多巴胺诱导的细胞死亡的抑制作用是多巴胺能细胞特异性的代偿反应，与其积聚和重新分布到核周区域有关，而不是与蛋白酶体系统有关。
Manganese as environmental factor is considered to cause parkinsonism and induce endoplasmic reticulum stress-mediated dopaminergic cell death. We examined the effects of manganese on parkin, identified as the gene responsible for familial Parkinson's disease, and the role of parkin in manganese-induced neuronal cell death. Manganese dose-dependently induced cell death of dopaminergic SH-SY5Y and CATH.a cells and cholinergic Neuro-2a cells, and that the former two cell types were more sensitive to manganese toxicity than Neuro-2a cells. Moreover, manganese increased the expression of endoplasmic reticulum stress-associated genes, including parkin, in SH-SY5Y cells and CATH.a cells, but not in Neuro-2a cells. Treatment with manganese resulted in accumulation of parkin protein in SH-SY5Y cells and its redistribution to the perinuclear region, especially aggregated Golgi complex, while in Neuro-2a cells neither expression nor redistribution of parkin was noted. Manganese showed no changes in proteasome activities in either cell. Transient transfection of parkin gene inhibited manganese- or manganese plus dopamine-induced cell death of SH-SY5Y cells, but not of Neuro-2a cells. Our results suggest that the attenuating effects of parkin against manganese- or manganese plus dopamine-induced cell death are dopaminergic cell-specific compensatory reactions associated with its accumulation and redistribution to perinuclear regions but not with proteasome system.