Li Xuping, Du Yunlan, Fan Xiaolan, Yang Dehua, Luo Guangrui, Le Weidong
Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Neuropathol Exp Neurol. 2008 Oct;67(10):933-44. doi: 10.1097/NEN.0b013e318186de64.
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 dopaminergic 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.
帕金森病的特征是黑质致密部多巴胺能神经元进行性丧失。有人提出泛素蛋白酶体系统功能障碍在帕金森病发病机制中起重要作用，但泛素蛋白酶体系统相关神经元变性的潜在机制尚不清楚。在此，我们证明蛋白酶体抑制剂乳胞素在体外可诱导c-Jun氨基末端激酶（JNK）和c-Jun磷酸化、细胞色素c释放、半胱天冬酶-9和半胱天冬酶-3激活以及多巴胺能神经元的顺序性凋亡。这些效应大多可被JNK抑制剂SP600125减弱。此外，在大鼠体内注入乳胞素也会在黑质神经元丧失之前导致JNK磷酸化；长期给予SP600125也可阻止这种丧失。这些结果表明JNK通过半胱天冬酶-3介导的凋亡途径参与蛋白酶体抑制诱导的多巴胺能神经元变性，提示该激酶可能是预防帕金森病患者黑质致密部变性的治疗靶点。
