K252A prevents DA cell death

K252A prevents DA cell death -...

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K252a Prevents Nigral Dopaminergic Cell Death Induced by 6-Hydroxydopamine through Inhibition of Both Mixed-Lineage Kinase 3/c-Jun NH 2 -Terminal Kinase 3 (JNK3) and Apoptosis- Inducing Kinase 1/JNK3 Signaling Pathways Jing Pan, Gang Wang, Hong-Qi Yang, Zhen Hong, Qin Xiao, Ru-Jing Ren, Hai-Yan Zhou, Li Bai, and Sheng-Di Chen Department of Neurology and Neuroscience Institute, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China (J.P., G.W., H.-Q.Y., Z.H., Q.X., R.-J.R., H.-Y.Z., L.B., S.-D.C.); and Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao-Tong University School of Medicine, Shanghai, China (J.P., H.-Q.Y., S.-D.C.) Received May 31, 2007; accepted September 11, 2007 ABSTRACT It is well documented that the mitogen-activated protein kinase pathway plays a pivotal role in rats with 6-hydroxydopamine (6-OHDA)-induced unilateral lesion in the nigrostriatal system. Our recent studies have shown that mixed-lineage kinase 3 (MLK3) and apoptosis-inducing kinase 1 (ASK1) are all involved in neuronal cell death induced by ischemia, which is mediated by the MLK3/ c-Jun NH 2 -terminal kinase 3 (JNK3) and ASK1/ JNK signaling pathway. To investigate whether these pathways are correlated with 6-OHDA-induced lesion as well, we exam- ined the phosphorylation of MLK3, ASK1, and JNK3 in 6-OHDA rats. The results showed that both MLK3 and ASK1 could activate JNK3 and then subsequently enhance the neuronal death through its downstream pathways (i.e., nuclear and non- nuclear pathway). K252a have wide-range effects including Trk inhibition, MLK3 inhibition, and activation of phosphatidylino- sitol 3 kinase and mitogen-activated protein kinase kinase sig- naling pathways through interactions with distinct targets and is a well known neuroprotective compound. We found that K252a could protect dopaminergic neurons against cell pro- gram death induced by 6-OHDA lesion, and the phenotypes of 6-OHDA rat model treated with K252a were partial rescued. The inhibition of K252a on the activation of MLK3/JNK3 and ASK1/JNK3 provided a link between 6-OHDA lesion and stress-activated kinases. It suggested that both proapoptotic MLK3/JNK3 and ASK1/JNK3 cascade may play an important role in dopaminergic neuronal death in 6-OHDA insult. Thus, the JNK3 signaling may eventually emerge as a prime target for novel therapeutic approaches to treatment of Parkinson dis- ease, and K252a may serve as a potential and important neu- roprotectant in therapeutic aspect in Parkinson disease. Although the expression of a number of cell death regula- tory genes and receptors have been investigated in the 6-OHDA lesion model, the exact molecular mechanisms of programed cell death underlying neurodegeneration remain poorly understood. The aim of recent studies has been set to identify the key components of the cell death machinery in dopaminergic neurons and to understand how intracellular signaling pathways regulate programmed cell death. The key components of the neuronal death machinery in-
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This note was uploaded on 01/07/2011 for the course BIPN BIPN 144 taught by Professor Bier during the Spring '10 term at UCSD.

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K252A prevents DA cell death -...

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