ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease.
ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease.
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DOI：
10.1016/j.ebiom.2017.07.024
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发表时间：
2017-08
期刊：
影响因子：
11.1
通讯作者：
Kakizuka A
中科院分区：
文献类型：
--
作者：
Nakano M;Imamura H;Sasaoka N;Yamamoto M;Uemura N;Shudo T;Fuchigami T;Takahashi R;Kakizuka A
帕金森病被认为是由大脑中受影响的多巴胺能神经元的线粒体功能障碍引起的。我们最近创造了一种小的化学物质，KUSs（京都大学物质），它可以减少细胞ATP的消耗。相比之下，雌激素受体相关受体（ers）的激动性配体有望通过增强ATP的产生来提高细胞ATP水平。在这里，我们证明了esculetin作为ERR激动剂的功能，并且将其添加到培养基中可以增强糖酵解和线粒体呼吸，导致细胞ATP水平升高。随后，我们在帕金森病模型中展示了KUSs、esculetin和GSK4716（一种ERRγ激动剂）对细胞死亡的神经保护作用。在存活的神经元中，ATP水平、α-突触核蛋白和CHOP（内质网应激介导的细胞死亡执行因子）的表达水平均得到纠正。我们建议通过抑制ATP消耗或增强ATP产生，或两者兼而有之来维持ATP水平，将是治疗帕金森病的一种有希望的治疗策略。我们描述了两种类型的ATP调节剂：一种限制ATP的消耗，而另一种增加ATP的产生。ATP调节因子维持ATP水平，保护神经元细胞免受内质网应激和最终的细胞死亡。ATP调节因子减轻帕金森病小鼠模型的疾病表型。ATP对人类活动和健康至关重要。我们假设维持ATP水平可能有助于在帕金森病（PD）等神经退行性疾病中保护脆弱的脑细胞。为此，我们开发并测试了两种类型的化合物，一种用于限制ATP的消耗，另一种用于提高ATP的产生。这些化学物质，我们称之为“ATP调节剂”，确实减轻了两种帕金森病小鼠模型的病理表型，表明ATP调节是目前无法治愈的疾病，如帕金森病，以及可能的其他神经退行性疾病的治疗策略。
Parkinson's disease is assumed to be caused by mitochondrial dysfunction in the affected dopaminergic neurons in the brain. We have recently created small chemicals, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption. By contrast, agonistic ligands of ERRs (estrogen receptor-related receptors) are expected to raise cellular ATP levels via enhancing ATP production. Here, we show that esculetin functions as an ERR agonist, and its addition to culture media enhances glycolysis and mitochondrial respiration, leading to elevated cellular ATP levels. Subsequently, we show the neuroprotective efficacies of KUSs, esculetin, and GSK4716 (an ERRγ agonist) against cell death in Parkinson's disease models. In the surviving neurons, ATP levels and expression levels of α-synuclein and CHOP (an ER stress-mediated cell death executor) were all rectified. We propose that maintenance of ATP levels, by inhibiting ATP consumption or enhancing ATP production, or both, would be a promising therapeutic strategy for Parkinson's disease. We describe two types of ATP regulators: one limits ATP consumption, while the other enhances ATP production. ATP regulators maintain ATP levels and protect neuronal cells from ER stress and eventual cell death. ATP regulators mitigate disease phenotypes in mouse models of Parkinson's disease. ATP is essential in human activities and health. We hypothesize that maintaining ATP levels may help to preserve vulnerable brain cells in neurodegenerative diseases like Parkinson's disease (PD). For this purpose, we developed and tested two types of chemical compounds, one for limiting ATP consumption and the other for enhancing ATP production. These chemicals, which we call “ATP regulators”, indeed mitigated the pathological phenotypes in two mouse models of PD, indicating that ATP regulation is a promising therapeutic strategy for currently incurable diseases, such as PD, and possibly other neurodegenerative diseases.
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