Departamento de Genética, Facultad CC Biológicas, Universidad de Valencia, 46100, Burjassot, Spain.
Instituto Universitario de Biotecnología Y Biomedicina (BIOTECMED), Universidad de Valencia, 46100, Burjassot, Spain.
Neurotherapeutics. 2021 Oct;18(4):2565-2578. doi: 10.1007/s13311-021-01134-2. Epub 2021 Oct 25.
Dopamine replacement represents the standard therapy for Parkinson's disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood-brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials.
多巴胺替代疗法是治疗帕金森病 (PD) 的标准疗法，PD 是一种常见的、慢性的、无法治愈的神经退行性疾病；然而，这种方法只能治疗这种毁灭性疾病的症状。在寻找针对其他相关分子和细胞机制的新型疾病修饰疗法的过程中，由于存在复杂的中枢神经系统、血脑屏障和与人类相似的神经递质谱，果蝇已成为研究神经退行性疾病的宝贵工具。人类 PD 相关基因在果蝇中也表现出保守性；DJ-1β 是 DJ-1 的果蝇同源物，DJ-1 基因的突变会导致早发性隐性 PD。有趣的是，DJ-1β 突变的果蝇表现出与 PD 相关的表型，包括运动缺陷、高水平氧化应激 (OS) 和代谢改变。为了寻找治疗 PD 的新疗法，我们使用 DJ-1β 突变果蝇和 Prestwick®化学库中的化合物进行了体内高通量筛选试验。在 DJ-1 缺陷的人类神经样细胞中验证了改善 DJ-1β 突变果蝇运动表现的药物，结果表明扎普司特具有抑制 OS 诱导的细胞死亡的最显著能力。扎普司特抑制磷酸二酯酶并激活 GPR35，这是一种以前与 PD 无关的孤儿 G 蛋白偶联受体。我们发现，扎普司特通过几种疾病修饰机制在果蝇和人类 PD 模型中发挥其有益作用，包括降低 OS 水平、减弱细胞凋亡、增加线粒体活力和增强糖酵解。因此，我们的研究结果支持扎普司特作为未来临床试验中 PD 的潜在治疗药物。
