Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease
Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease
复制标题
鉴定用于改善家族性帕金森病神经元线粒体清除障碍的治疗药物
DOI：
10.1016/j.stemcr.2020.04.011
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发表时间：
2020
影响因子：
5.9
通讯作者：
Akamatsu Wado
中科院分区：
文献类型：
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作者：
Yamaguchi Akihiro;Ishikawa Kei-ichi;Inoshita Tsuyoshi;Shiba-Fukushima Kahori;Saiki Shinji;Hatano Taku;Mori Akio;Oji Yutaka;Okuzumi Ayami;Li Yuanzhe;Funayama Manabu;Imai Yuzuru;Hattori Nobutaka;Akamatsu Wado
帕金森病（Parkinson disease，PD）是一种以中脑多巴胺能神经元进行性缺失为主要表现的神经退行性疾病，其发病机制与线粒体功能障碍有关。本研究旨在建立一种基于成像的半自动高通量系统，用于定量检测来自具有ParkinorPINK1突变的家族性PD患者的诱导多能干细胞（iPSC）中多巴胺能神经元的疾病特异性表型，这些患者表现出异常的线粒体稳态。所提出的系统概括了这些家族性PD衍生神经元中线粒体清除、ROS积累和细胞凋亡增加的缺陷。我们筛选了320种化合物改善多种表型的能力，并确定了四种候选药物。这些药物中的一些改善了果蝇中PINK1失活引起的运动缺陷和减少ATP的产生，并且对线粒体清除受损的特发性PD衍生神经元有效。我们的研究结果表明，拟议的高通量系统有可能确定有效的药物治疗家族性和特发性PD。
Parkinson disease (PD) is a neurodegenerative disorder caused by the progressive loss of midbrain dopaminergic neurons, and mitochondrial dysfunction is involved in its pathogenesis. This study aimed to establish an imaging-based, semi-automatic, high-throughput system for the quantitative detection of disease-specific phenotypes in dopaminergic neurons from induced pluripotent stem cells (iPSCs) derived from patients with familial PD havingParkinorPINK1mutations, which exhibit abnormal mitochondrial homeostasis. The proposed system recapitulates the deficiency of mitochondrial clearance, ROS accumulation, and increasing apoptosis in these familial PD-derived neurons. We screened 320 compounds for their ability to ameliorate multiple phenotypes and identified four candidate drugs. Some of these drugs improved the locomotion defects and reduced ATP production caused by PINK1 inactivation inDrosophilaand were effective for idiopathic PD-derived neurons with impaired mitochondrial clearance. Our findings suggest that the proposed high-throughput system has potential for identifying effective drugs for familial and idiopathic PD.