A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons.
A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons.
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作者：
Kim GJ;Mo H;Liu H;Wu Z;Chen S;Zheng J;Zhao X;Nucum D;Shortland J;Peng L;Elepano M;Tang B;Olson S;Paras N;Li H;Renslo AR;Arkin MR;Huang B;Lu B;Sirota M;Guo S
帕金森病(PD)是一种常见的神经退行性疾病，缺乏有效的治疗方法。在这里，我们建立了一种适合于高含量筛选的线粒体功能障碍和健壮性的斑马鱼幼体多巴胺(DA)神经元化学消融模型。我们使用这个系统进行体内DA神经元成像的化学筛选，并确定肾素-血管紧张素-醛固酮系统(RAAS)抑制剂具有显著的神经保护作用。敲除DA神经元的血管紧张素受体1(Agtr1)揭示了一种细胞自主的神经保护机制。DA神经元特异性RNA-SEQ识别线粒体途径基因的表达，该基因可通过RAAS抑制剂治疗显着恢复。在斑马鱼高谢病模型和果蝇PINK1缺陷性帕金森病模型中进一步观察了RAAS抑制剂的神经保护作用。最后，对临床数据的检查显示，RAAS抑制剂在延缓PD进展方面有显著作用。我们的发现揭示了以RAAS通路为靶点进行神经保护的治疗潜力和机制，并展示了一种将基础科学与转化医学联系起来的显著方法。帕金森氏症是由脑细胞的缓慢死亡和退化引起的，特别是产生一种名为多巴胺的化学信使的神经元。某些药物可以缓解由此导致的多巴胺水平的下降，并有助于控制症状，但它们会产生危险的副作用。没有任何治疗方法可以减缓或阻止这种疾病的进展，这种疾病影响着全球0.3%的人口。帕金森氏症的出现有许多因素，包括遗传因素和环境因素。例如，线粒体功能障碍是一种已知的与产生多巴胺的神经元死亡有关的机制。线粒体是为细胞提供动力的内部结构。斑马鱼是一种可以用来研究帕金森氏症的小鱼，因为它们在实验室里很容易操作，并且与人类有许多共同的特征。特别是，它们可以帮助测试各种潜在药物对这种情况的影响。在这里，Kim等人。他们建立了一个新的斑马鱼模型，在该模型中，产生多巴胺的脑细胞由于线粒体不能正常工作而死亡；然后，他们使用这种测试来评估1,403种不同化学物质对这些细胞完整性的影响。一组被称为肾素-血管紧张素-醛固酮(RAAS)抑制剂的分子被证明可以保护产生多巴胺的神经元，并阻止它们经常死亡。这些药物已经被用于治疗高血压，因为它们有助于扩张血管。然而，在大脑中，RAAS通过恢复某些线粒体过程来发挥作用。Kim等人。然后调查了这些结果是否与其他更广泛的背景相关。他们能够证明RAAS抑制剂在其他动物身上也有同样的效果，而且已经服用这些药物治疗高血压的患者帕金森病的进展通常会更慢。综上所述，这些发现因此表明，RAAS抑制剂可能对治疗帕金森氏症以及其他因线粒体不正常工作而出现的大脑疾病有用。需要临床研究和改进这些药物的新方法，以进一步研究和利用这些潜在的好处。
Parkinson’s disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine. Parkinson’s disease is caused by the slow death and deterioration of brain cells, in particular of the neurons that produce a chemical messenger known as dopamine. Certain drugs can mitigate the resulting drop in dopamine levels and help to manage symptoms, but they cause dangerous side-effects. There is no treatment that can slow down or halt the progress of the condition, which affects 0.3% of the population globally. Many factors, both genetic and environmental, contribute to the emergence of Parkinson’s disease. For example, dysfunction of the mitochondria, the internal structures that power up cells, is a known mechanism associated with the death of dopamine-producing neurons. Zebrafish are tiny fish which can be used to study Parkinson’s disease, as they are easy to manipulate in the lab and share many characteristics with humans. In particular, they can be helpful to test the effects of various potential drugs on the condition. Here, Kim et al. established a new zebrafish model in which dopamine-producing brain cells die due to their mitochondria not working properly; they then used this assay to assess the impact of 1,403 different chemicals on the integrity of these cells. A group of molecules called renin-angiotensin-aldosterone (RAAS) inhibitors was shown to protect dopamine-producing neurons and stopped them from dying as often. These are already used to treat high blood pressure as they help to dilate blood vessels. In the brain, however, RAAS worked by restoring certain mitochondrial processes. Kim et al. then investigated whether these results are relevant in other, broader contexts. They were able to show that RAAS inhibitors have the same effect in other animals, and that Parkinson’s disease often progresses more slowly in patients that already take these drugs for high blood pressure. Taken together, these findings therefore suggest that RAAS inhibitors may be useful to treat Parkinson’s disease, as well as other brain illnesses that emerge because of mitochondria not working properly. Clinical studies and new ways to improve these drugs are needed to further investigate and capitalize on these potential benefits.