c-Jun N-terminal kinase mediates lactacystin-induced dopamine neuron degeneration
c-Jun N-terminal kinase mediates lactacystin-induced dopamine neuron degeneration
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DOI：
10.1097/nen.0b013e318186de64
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发表时间：
2008-10-01
影响因子：
3.2
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Li, Xuping;Du, Yunlan;Le, Weidong
帕金森病的特征在于黑质延髓部多巴胺能神经元的进行性丧失。泛素蛋白酶体系统的功能障碍在帕金森病的发病机制中起着重要作用，但泛素蛋白酶体系统相关的神经元变性的机制尚不清楚。在这里，我们证明了蛋白酶体抑制剂lactacystin诱导c-Jun N-末端激酶（JNK）和c-Jun的磷酸化，细胞色素c的释放，caspase-9和caspase-3的激活，以及体外多巴胺能神经元的顺序凋亡。这些作用中的大多数可以被JNK抑制剂SP 600125减弱。此外，在大鼠体内输注lactacystin也导致黑质神经元损失之前JNK的磷酸化;长期施用SP 600125也阻断这种损失。这些结果表明，JNK参与蛋白酶体抑制诱导的多巴胺能神经元变性通过caspase-3介导的凋亡途径，这表明这种激酶可能是一个治疗靶点，用于预防帕金森病患者的黑质黑部延髓变性。
Parkinson disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been proposed that dysfunction of the ubiquitin proteasome system plays an important role in the pathogenesis of Parkinson disease, but the mechanisms underlying ubiquitin proteasome system-related neuron degeneration are unknown. Here, we demonstrate that the proteasome inhibitor lactacystin induces phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, the release of cytochrome c, activation of both caspase-9 and caspase-3, and sequential apoptosis of dopaminergic neurons in vitro. Most of these effects can be attenuated by the JNK inhibitor SP600125. Furthermore, infusion of lactacystin in rats in vivo also leads to phosphorylation of JNK before nigral neuron loss; chronic administration of SP600125 also blocks this loss. These results indicate that JNK is involved in proteasome inhibition-induced doparninergic neuron degeneration through caspase-3-mediated apoptotic pathways, suggesting that this kinase may be a therapeutic target for the prevention of substantia nigra pars compacta degeneration in Parkinson disease patients.