Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models
Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models
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DOI：
10.1016/j.cmet.2019.08.023
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发表时间：
2019-12-03
期刊：
影响因子：
29
通讯作者：
Wang, Xinnan
中科院分区：
文献类型：
--
作者：
Hsieh, Chung-Han;Li, Li;Wang, Xinnan
帕金森病（PD）分子靶点和药效学标志物的鉴定将为更有效的临床管理和实验治疗提供支持。Miro1定位于线粒体表面，介导线粒体运动。Miro1从去极化线粒体中移除，以促进线粒体自噬的清除。在这里，我们探讨了Miro1在检测PD和衡量潜在治疗方法方面的临床应用。我们利用生物化学方法测量了PD患者皮肤成纤维细胞对线粒体去极化的反应，发现超过94%的患者成纤维细胞系在去极化后不能去除Miro1。我们发现一个小分子可以修复PD成纤维细胞中Miro1的缺陷。用这种化合物治疗病人来源的神经元和苍蝇模型可以拯救运动缺陷和多巴胺能神经变性。我们的研究结果表明，追踪这种Miro1标记物并参与基于Miro1的治疗可以为个性化医疗开辟新的途径。
The identification of molecular targets and pharmacodynamic markers for Parkinson's disease (PD) will empower more effective clinical management and experimental therapies. Miro1 is localized on the mitochondrial surface and mediates mitochondrial motility. Miro1 is removed from depolarized mitochondria to facilitate their clearance via mitophagy. Here, we explore the clinical utility of Miro1 for detecting PD and for gauging potential treatments. We measure the Miro1 response to mitochondrial depolarization using biochemical assays in skin fibroblasts from a broad spectrum of PD patients and discover that more than 94% of the patients' fibroblast cell lines fail to remove Miro1 following depolarization. We identify a small molecule that can repair this defect of Miro1 in PD fibroblasts. Treating patient-derived neurons and fly models with this compound rescues the locomotor deficits and dopaminergic neurodegeneration. Our results indicate that tracking this Miro1 marker and engaging in Miro1 -based therapies could open new avenues to personalized medicine.