Department of Pharmacology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
Neurosci Lett. 2012 Sep 13;525(2):83-8. doi: 10.1016/j.neulet.2012.07.030. Epub 2012 Aug 9.
Dickkopf-1 (Dkk1), an antagonist of the Wnt/β-catenin pathway, has been implicated in many neurodegenerative diseases. However, it's unknown whether Dkk1 is involved in the pathogenesis of Parkinson's disease. In this study, we discovered that Dkk1 was increased in 6-hydroxydopamin(6-OHDA)-lesioned rats. In the meanwhile, inhibition of the canonical Wnt signaling pathway, including the activation of glycogen synthase kinase-3β (GSK-3β) and decrease of β-catenin, was also found in 6-OHDA-lesioned rats. Treatment with rhDkk1 aggravated the dopaminergic neuron damage of the substantia nigra and the inhibition of the canonical Wnt signaling pathway in 6-OHDA-lesioned rats, while the above effects in these rats were abolished by pretreatment with LiCl, an inhibitor of GSK-3β, for consecutive 7 d. These data suggest that Dkk1 plays an important role in the etiology of PD models and it contributes to the neurodegeneration in 6-OHDA-lesioned rats via inhibition of the canonical Wnt pathway.
Dickkopf-1（Dkk1）是 Wnt/β-catenin 通路的拮抗剂，它与许多神经退行性疾病有关。然而，Dkk1 是否参与帕金森病的发病机制尚不清楚。在这项研究中，我们发现 6-羟多巴胺（6-OHDA）损伤大鼠中 Dkk1 增加。同时，6-OHDA 损伤大鼠中也发现了经典 Wnt 信号通路的抑制，包括糖原合成激酶-3β（GSK-3β）的激活和 β-catenin 的减少。用 rhDkk1 处理加重了 6-OHDA 损伤大鼠黑质多巴胺能神经元的损伤和经典 Wnt 信号通路的抑制，而连续 7 天用 GSK-3β抑制剂 LiCl 预处理则消除了这些大鼠的上述作用。这些数据表明，Dkk1 在 PD 模型的发病机制中起重要作用，它通过抑制经典 Wnt 通路促进 6-OHDA 损伤大鼠的神经退行性变。
