A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling
A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling
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基于细胞的高通量筛选鉴定出两种增强 PINK1-Parkin 信号转导的化合物
DOI：
10.1016/j.isci.2020.101048
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发表时间：
2020
期刊：
影响因子：
5.8
通讯作者：
Hattori Nobutaka
中科院分区：
文献类型：
--
作者：
Shiba-Fukushima Kahori;Inoshita Tsuyoshi;Sano Osamu;Iwata Hidehisa;Ishikawa Kei-ichi;Okano Hideyuki;Akamatsu Wado;Imai Yuzuru;Hattori Nobutaka
早发性帕金森病相关PINK 1-Parkin信号传导维持线粒体健康增强PINK 1-Parkin信号传导的治疗方法为治疗由线粒体功能障碍引起的各种疾病提供了潜在的策略。我们报告了两个PINK 1-Parkin信号传导的化学增强剂，使用一个强大的基于细胞的高通量筛选系统进行鉴定。这些小分子T0466和T0467在低剂量下激活多巴胺能神经元和成肌细胞中的Parkin线粒体易位，而不诱导PINK 1的线粒体积累。此外，这两种化合物都降低了未折叠的线粒体蛋白水平，可能是通过增强PINK 1-Parkin信号传导。这些分子还通过降低果蝇PINK 1活性减轻运动缺陷、ATP产生减少和肌肉中线粒体Ca 2+反应的干扰以及多巴胺能神经元中线粒体聚集的沿着。我们的研究结果表明，T0466和T0467可能有希望作为帕金森病和相关疾病的治疗试剂。
Early-onset Parkinson's disease-associated PINK1-Parkin signaling maintains mitochondrial health. Therapeutic approaches for enhancing PINK1-Parkin signaling present a potential strategy for treating various diseases caused by mitochondrial dysfunction. We report two chemical enhancers of PINK1-Parkin signaling, identified using a robust cell-based high-throughput screening system. These small molecules, T0466 and T0467, activate Parkin mitochondrial translocation in dopaminergic neurons and myoblasts at low doses that do not induce mitochondrial accumulation of PINK1. Moreover, both compounds reduce unfolded mitochondrial protein levels, presumably through enhanced PINK1-Parkin signaling. These molecules also mitigate the locomotion defect, reduced ATP production, and disturbed mitochondrial Ca2+response in the muscles along with the mitochondrial aggregation in dopaminergic neurons through reduced PINK1 activity inDrosophila. Our results suggested that T0466 and T0467 may hold promise as therapeutic reagents in Parkinson's disease and related disorders.
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DOI：
10.3791/60233
发表时间：
2019
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Matthew J. Davis;Danielle E. Talbot;Jennifer C Jemc
通讯作者：
Jennifer C Jemc
DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K
影响因子：
16
作者：
Heo JM;Ordureau A;Paulo JA;Rinehart J;Harper JW
通讯作者：
Harper JW
DOI：
10.1073/pnas.1523926113
发表时间：
2016-04-12
影响因子：
11.1
作者：
Richter, Benjamin;Sliter, Danielle A.;Dikic, Ivan
通讯作者：
Dikic, Ivan
PINK1在线粒体受损中有选择地稳定以激活帕金。
影响因子：
9.8
作者：
Narendra DP;Jin SM;Tanaka A;Suen DF;Gautier CA;Shen J;Cookson MR;Youle RJ
通讯作者：
Youle RJ