Induction of KLF4 Contributes to the Neurotoxicity of MPP + in M17 Cells: A New Implication in Parkinson's Disease
Induction of KLF4 Contributes to the Neurotoxicity of MPP + in M17 Cells: A New Implication in Parkinson's Disease
复制标题
DOI：
10.1007/s12031-013-9961-3
复制
发表时间：
2013-09-01
影响因子：
3.1
通讯作者：
Ge, Ruli
中科院分区：
文献类型：
--
作者：
Chen, Jinbo;Wang, Xuezhen;Ge, Ruli
帕金森病(PD)是人类第二常见的神经退行性疾病。Kruppel样因子(KLF)4在帕金森病中的作用尚不清楚。本研究发现，1-甲基-4-苯基吡啶(MPP+)与人神经母细胞瘤M17细胞孵育后，KLF4的表达呈时间和剂量依赖性增加，提示KLF4在MPP+诱导的神经毒性中可能起一定作用。随后的实验表明，KLF4在M17细胞中的过表达促进了MPP+诱导的氧化应激，表现为加剧了活性氧、4-羟基-2-壬烯醛和蛋白质羰基。此外，KLF4过表达可减缓细胞增殖，促进乳酸脱氢酶释放。相反，抑制M17细胞中的KLF4可减轻MPP+诱导的神经毒性。KLF4过表达后，超氧化物歧化酶(SOD)1在mRNA和蛋白水平的表达均降低，而KLF4基因被敲除后，超氧化物歧化酶1的表达增加。此外，启动子荧光素酶实验表明，KLF4抑制了SOD1的转录活性。以上结果表明，KLF4通过抑制SOD1的转录而增强MPP+的神经毒性，提示KLF4可能是帕金森病氧化应激和细胞死亡增加的机制之一。
Parkinson's disease (PD) is the second most common neurodegenerative disease in humans. The effect of Kruppel-like factor (KLF) 4 in PD is unknown. In this study, KLF4 was found to be increased in both a time-dependent manner and a dose-dependent manner in response to the incubation with 1-methyl-4-phenylpyridinium (MPP+) in human dopamine neuroblastoma M17 cells, suggesting a potential role in MPP + -induced neurotoxicity. Following experiments showed that overexpression of KLF4 in M17 cells promoted MPP + -induced oxidative stress, embodied by exacerbated reactive oxygen species, 4-hydroxy-2-nonenal, and protein carbonyls. Furthermore, overexpression of KLF4 slowed cell proliferation and promoted lactate dehydrogenase release. Conversely, inhibition of KLF4 in M17 cells attenuated MPP + -induced neurotoxicity. The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4. Moreover, promoter luciferase experiments showed that transcriptional activity on SOD1 was inhibited by KLF4. All the results indicated that KLF4 promoted the neurotoxicity of MPP + via inhibiting the transcription of SOD1, suggesting a potential mechanism of increased oxidative stress and cell death in Parkinson's disease.