Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): Implications for neurodegeneration in Parkinson's disease.
Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): Implications for neurodegeneration in Parkinson's disease.
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DOI：
10.1186/1756-6606-1-12
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发表时间：
2008-10-22
期刊：
影响因子：
3.6
通讯作者：
Kanthasamy A
中科院分区：
文献类型：
--
作者：
Kanthasamy AG;Kitazawa M;Yang Y;Anantharam V;Kanthasamy A
在以前的工作中，我们研究了狄氏剂的细胞毒性和多巴胺能PC 12细胞的信号细胞死亡机制。狄氏剂是与帕金森氏病相关的环境因素之一，可选择性破坏多巴胺能神经元。在这里，我们进一步研究狄氏剂的毒性在多巴胺能神经元细胞模型的帕金森氏病，即N27细胞，使用生化，免疫化学和流式细胞仪分析。在这项研究中，狄氏剂处理的N27细胞经历了一个快速和显着的活性氧增加，然后细胞色素c释放到胞质溶胶。胞浆细胞色素c激活caspase-3依赖的凋亡途径，增加caspase-3的活性，观察到以下3小时狄氏剂暴露在剂量依赖性的方式。此外，狄氏剂引起N27细胞和脑切片中蛋白激酶C δ（PKCδ）的半胱天冬酶依赖性蛋白水解裂解为41 kDa催化亚基和38 kDa调节亚基。PKCδ在狄氏醇处理的多巴胺能神经元细胞中执行凋亡过程中起关键作用，因为用PKCδ抑制剂rottlerin预处理，或转染和过表达催化失活的PKCδ K376 R，显著减弱狄氏醇诱导的DNA断裂和染色质凝聚。总之，我们得出结论，caspase-3依赖的蛋白水解激活PKCδ是一个关键的事件，狄氏剂诱导的多巴胺能神经元细胞凋亡。
In previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons. Here we further investigated dieldrin toxicity in a dopaminergic neuronal cell model of Parkinson's disease, namely N27 cells, using biochemical, immunochemical, and flow cytometric analyses. In this study, dieldrin-treated N27 cells underwent a rapid and significant increase in reactive oxygen species followed by cytochrome c release into cytosol. The cytosolic cytochrome c activated caspase-dependent apoptotic pathway and the increased caspase-3 activity was observed following a 3 hr dieldrin exposure in a dose-dependent manner. Furthermore, dieldrin caused the caspase-dependent proteolytic cleavage of protein kinase C delta (PKCδ) into 41 kDa catalytic and 38 kDa regulatory subunits in N27 cells as well as in brain slices. PKCδ plays a critical role in executing the apoptotic process in dieldrin-treated dopaminergic neuronal cells because pretreatment with the PKCδ inhibitor rottlerin, or transfection and over-expression of catalytically inactive PKCδK376R, significantly attenuates dieldrin-induced DNA fragmentation and chromatin condensation. Together, we conclude that caspase-3-dependent proteolytic activation of PKCδ is a critical event in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells.
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DOI：
10.3181/00379727-136-35352
发表时间：
1971-01-01
影响因子：
--
作者：
BERGEN, WG
通讯作者：
BERGEN, WG
影响因子：
3.5
作者：
BLOOMQUIST, JR
通讯作者：
BLOOMQUIST, JR
影响因子：
3.8
作者：
GANT, DB;ELDEFRAWI, ME;ELDEFRAWI, AT
通讯作者：
ELDEFRAWI, AT
影响因子：
9.9
作者：
Langston, JW
通讯作者：
Langston, JW
DOI：
10.1196/annals.1332.017
发表时间：
2004-01-01
期刊：
PROTECTIVE STRATEGIES FOR NEURODEGENERATIVE DISEASES
影响因子：
--
作者：
Anantharam, V;Kitazawa, M;Kanthasamy, AG
通讯作者：
Kanthasamy, AG