品脱1
帕金
多巴胺能
生物
帕金森病
表型
线粒体
诱导多能干细胞
疾病
神经科学
生物信息学
细胞生物学
多巴胺
病理
遗传学
医学
基因
胚胎干细胞
作者
Akihiro Yamaguchi,Keiichi Ishikawa,Tsuyoshi Inoshita,Kahori Shiba‐Fukushima,Sachio Saiki,Taku Hatano,Akio Mori,Yusuke Oji,Ayami Okuzumi,Yuanzhe Li,Manabu Funayama,Yuzuru Imai,Nobutaka Hattori,Wado Akamatsu
标识
DOI:10.1016/j.stemcr.2020.04.011
摘要
Summary
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 having Parkin or PINK1 mutations, 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 in Drosophila and 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.
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