Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease
Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease
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DOI：
10.1073/pnas.181182298
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发表时间：
2001-08-28
影响因子：
11.1
通讯作者：
Schulz, JB
中科院分区：
文献类型：
--
作者：
Xia, XG;Harding, T;Schulz, JB
越来越多的证据表明，细胞凋亡可能是帕金森病多巴胺能神经元选择性丧失的潜在细胞死亡机制。由于半胱天冬酶的抑制在帕金森病的1-甲基-4-苯基-1，2，3，6-四氢吡啶/1-甲基-4-苯基吡啶（MPTP/MPP+）模型中仅提供部分保护，我们研究了促凋亡c-Jun N-末端激酶（JNK）信号级联在体外和小鼠体内SH-SY 5 Y人神经母细胞瘤细胞中的作用。MPTP/MPP+导致JNK激酶（MKK 4）、INK和c-Jun的顺序磷酸化和激活，半胱天冬酶的激活和凋亡。在小鼠中，JNK相互作用蛋白-1（一种支架蛋白和INK抑制剂）的INK结合结构域的腺病毒基因转移抑制了MKK 4磷酸化下游的级联反应，阻断了JNK，c-Jun和caspase的激活，多巴胺能神经元的死亡以及纹状体中儿茶酚胺的损失。此外，基因转移导致行为益处。因此，抑制INK通路为帕金森病提供了一种新的治疗策略，其阻断多巴胺能神经元中细胞凋亡执行上游的死亡信号传导通路，提供了优于直接抑制半胱天冬酶的治疗优势。
Increasing evidence suggests that apoptosis may be the underlying cell death mechanism in the selective loss of dopaminergic neurons in Parkinson's disease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP+ led to the sequential phosphorylation and activation of JNK kinase (MKK4), INK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the INK binding domain of JNK-interacting protein-1 (a scaffold protein and inhibitor of INK) inhibited this cascade downstream of MKK4 phosphorylation, blocked JNK, c-Jun, and caspase activation, the death of dopaminergic neurons, and the loss of catecholamines in the striatum. Furthermore, the gene transfer resulted in behavioral benefit. Therefore, inhibition of the INK pathway offers a new treatment strategy for Parkinson's disease that blocks the death signaling pathway upstream of the execution of apoptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases.