Departamento de Genética, Facultad CC Biológicas, Universidad de Valencia, 46100 Burjassot, Spain; Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain.
Departamento de Genética, Facultad CC Biológicas, Universidad de Valencia, 46100 Burjassot, Spain.
Free Radic Biol Med. 2017 Jul;108:683-691. doi: 10.1016/j.freeradbiomed.2017.04.364. Epub 2017 Apr 25.
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5-10% of them are familial forms caused by mutations in certain genes. One of these genes is the DJ-1 oncogene, which is involved in an early-onset recessive PD form. Currently, PD is an incurable disease for which existing therapies are not sufficiently effective to counteract or delay the progression of the disease. Therefore, the discovery of alternative drugs for the treatment of PD is essential. In this study we used a Drosophila PD model to identify candidate compounds with therapeutic potential for this disease. These flies carry a loss-of-function mutation in the DJ-1β gene, the Drosophila ortholog of human DJ-1, and show locomotor defects reflected by a reduced climbing ability. A pilot modifier chemical screen was performed, and several candidate compounds were identified based on their ability to improve locomotor activity of PD model flies. We demonstrated that some of them were also able to reduce OS levels in these flies. To validate the compounds identified in the Drosophila screen, a human cell PD model was generated by knocking down DJ-1 function in SH-SY5Y neuroblastoma cells. Our results showed that some of the compounds were also able to increase the viability of the DJ-1-deficient cells subjected to OS, thus supporting the use of Drosophila for PD drug discovery. Interestingly, some of them have been previously proposed as alternative therapies for PD or tested in clinical trials and others are first suggested in this study as potential drugs for the treatment of this disease.
帕金森病（PD）是仅次于阿尔茨海默病的第二大常见神经退行性疾病。它是由黑质致密部多巴胺能神经元丧失引起的，导致纹状体中多巴胺水平下降，从而产生运动障碍。PD 神经退行性变的主要生理原因是氧化应激（OS）和线粒体功能障碍；这些病理生理变化既可以由遗传因素引起，也可以由环境因素引起。虽然大多数 PD 病例是散发性的，但已经表明其中 5-10%是由某些基因突变引起的家族形式。这些基因之一是 DJ-1 癌基因，它参与了一种早发性隐性 PD 形式。目前，PD 是一种无法治愈的疾病，现有的治疗方法不足以有效对抗或延缓疾病的进展。因此，发现治疗 PD 的替代药物至关重要。在这项研究中，我们使用了一种果蝇 PD 模型来鉴定具有治疗这种疾病潜力的候选化合物。这些果蝇携带 DJ-1β 基因的功能丧失突变，DJ-1β 是人类 DJ-1 的果蝇同源物，表现出运动缺陷，反映在攀爬能力下降。进行了初步的修饰化学筛选，并根据改善 PD 模型果蝇运动活性的能力鉴定了几种候选化合物。我们证明，其中一些化合物还能够降低这些果蝇的 OS 水平。为了验证在果蝇筛选中鉴定出的化合物，通过敲低 DJ-1 功能在 SH-SY5Y 神经母细胞瘤细胞中生成了人类细胞 PD 模型。我们的结果表明，其中一些化合物还能够提高 OS 下 DJ-1 缺失细胞的活力，从而支持使用果蝇进行 PD 药物发现。有趣的是，其中一些化合物以前曾被提议作为 PD 的替代疗法或在临床试验中进行过测试，而另一些则是在这项研究中首次被提议作为治疗这种疾病的潜在药物。
