Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. PARK2 mutations cause early-onset Parkinson's disease (EO-PD). PARK2 encodes an E3 ubiquitin ligase, Parkin. Extensive in vitro studies and cell line characterization have shown that Parkin is required for mitophagy, but the physiological pathology and context of the pathway remain unknown. In general, monogenic Parkin knockout mice do not accurately reflect human PD symptoms and exhibit no signs of dopaminergic (DA) neurodegeneration. To assess the critical role of Parkin-mediated mitophagy in DA neurons, we characterized Parkin knockout mice over a long period of time. At the age of 110 weeks, Parkin knockout mice exhibited locomotor impairments, including hindlimb defects and neuronal loss. In their DA neurons, fragmented mitochondria with abnormal internal structures accumulated. The age-related motor dysfunction and damaged mitochondria pathology in Parkin-deficient mice suggest that impairment of mitochondrial clearance may underlie the pathology of PD.

中文翻译：

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Parkin的丢失会导致衰老小鼠的线粒体更新和多巴胺能神经元丢失。

帕金森氏病（PD）是第二大最常见的神经退行性疾病，其特征是黑纹状体多巴胺神经元丢失。PARK2突变会导致帕金森氏病（EO-PD）提前发作。PARK2编码E3泛素连接酶Parkin。广泛的体外研究和细胞系表征表明，线粒体需要帕金蛋白，但是该路径的生理病理学和背景仍然未知。通常，单基因帕金森基因敲除小鼠不能准确反映人的PD症状，也没有多巴胺能（DA）神经变性的迹象。为了评估帕金介导的线粒体在DA神经元中的关键作用，我们在很长一段时间内表征了帕金敲除小鼠。在110周龄时，Parkin基因敲除小鼠表现出运动障碍，包括后肢缺陷和神经元丢失。在其DA神经元中，线粒体破碎，内部结构异常积累。帕金缺乏症小鼠的年龄相关运动功能障碍和线粒体病理受损提示线粒体清除障碍可能是PD病理的基础。