Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, PR China.
Neurobiol Dis. 2012 Sep;47(3):385-92. doi: 10.1016/j.nbd.2012.05.020. Epub 2012 Jun 2.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is believed to involve both genetic susceptibility and environmental factors. Mutations in Leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD, and the LRRK2 locus contributes to sporadic PD. Environmental toxins are believed to act in part by causing oxidative stress. Here we employed cell and Drosophila models to investigate the interaction between LRRK2 genetic mutations and oxidative stress. We found that H(2)O(2) increased LRRK2 kinase activity and enhanced LRRK2 cell toxicity in cultured cells and mouse primary cortical neurons. Furthermore, a sub-toxic dose of H(2)O(2) significantly shortened the survival of LRRK2 transgenic flies and augmented LRRK2-induced locomotor defects and dopamine neuron loss. Treatment with a LRRK2 kinase inhibitor (GW5074) or an anti-oxidant (curcumin) significantly suppressed these PD-like phenotypes in flies. Moreover, curcumin significantly reduced LRRK2 kinase activity and the levels of oxidized proteins, and thus acted as not only an antioxidant but also a LRRK2 kinase inhibitor. These results indicate that LRRK2 genetic alterations can interact with oxidative stress, converging on a pathogenic pathway that may be related to PD. These studies also identified curcumin as a LRRK2 kinase inhibitor that may be a useful candidate for LRRK2-linked PD intervention.
帕金森病（PD）是一种神经退行性疾病，其特征是多巴胺能神经元选择性丧失和路易体的存在。PD 的发病机制被认为涉及遗传易感性和环境因素。富亮氨酸重复激酶 2（LRRK2）突变导致遗传形式的 PD，LRRK2 基因座与散发性 PD 有关。环境毒素被认为部分通过引起氧化应激而起作用。在这里，我们使用细胞和果蝇模型来研究 LRRK2 基因突变与氧化应激之间的相互作用。我们发现 H₂O₂增加了 LRRK2 激酶活性，并增强了培养细胞和小鼠原代皮质神经元中的 LRRK2 细胞毒性。此外，亚毒性剂量的 H₂O₂显著缩短了 LRRK2 转基因果蝇的寿命，并加剧了 LRRK2 诱导的运动缺陷和多巴胺神经元丢失。用 LRRK2 激酶抑制剂（GW5074）或抗氧化剂（姜黄素）处理可显著抑制果蝇中的这些 PD 样表型。此外，姜黄素显著降低了 LRRK2 激酶活性和氧化蛋白水平，因此不仅是一种抗氧化剂，也是一种 LRRK2 激酶抑制剂。这些结果表明，LRRK2 基因突变可以与氧化应激相互作用，汇聚在一条可能与 PD 相关的致病途径上。这些研究还确定了姜黄素作为 LRRK2 激酶抑制剂，可能是 LRRK2 相关 PD 干预的有用候选药物。
