In 2018, we summarized Parkin mutation analysis over the 20 years since its discovery. As a strategy for treating Parkinson's disease (PD), disease-modifying therapies based on the overall picture of PD, including pathological studies of hereditary PD, have been developed. With the discovery of Parkin, research on PD accelerated explosively around the world. Several PD mouse models were generated to investigate the pathology of PD. Recently, we reported dopaminergic neuron-specific autophagy-deficient mice as a model of sporadic PD. These mice exhibit Lewy pathology and motor dysfunction, and provide in vivo evidence for Lewy body formation. In these animals, synuclein deposition is preceded by p62, resulting in the formation of inclusions containing both proteins. The number and size of these inclusions increase gradually with aging. Consequently, dopaminergic (DA) neuron loss and motor dysfunction are observed in 120-week-old mice. To assess the critical role of Parkin in vivo, 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, and fragmented mitochondria with abnormal internal structures accumulated in their DA neurons. Age-related motor dysfunction and damaged mitochondria were observed in Parkin-deficient mice.

中文翻译：

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对 Parkin 相关模型小鼠的致病性见解

2018 年，我们总结了自发现以来 20 年来的 Parkin 突变分析。作为治疗帕金森病 (PD) 的策略，已经开发了基于 PD 整体情况的疾病修饰疗法，包括遗传性 PD 的病理学研究。随着 Parkin 的发现，全球对 PD 的研究呈爆炸性加速。生成了几个 PD 小鼠模型来研究 PD 的病理。最近，我们报道了多巴胺能神经元特异性自噬缺陷小鼠作为散发性 PD 模型。这些小鼠表现出路易病理和运动功能障碍，并为路易小体形成提供体内证据。在这些动物中，突触核蛋白沉积在 p62 之前，导致形成含有两种蛋白质的内含物。这些夹杂物的数量和大小随着老化而逐渐增加。因此，在 120 周大的小鼠中观察到多巴胺能 (DA) 神经元丢失和运动功能障碍。为了评估 Parkin 在体内的关键作用，我们在很长一段时间内对 Parkin 基因敲除小鼠进行了表征。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，以及在其 DA 神经元中积累异常内部结构的线粒体碎片化。在 Parkin 缺陷小鼠中观察到与年龄相关的运动功能障碍和线粒体受损。以及在其 DA 神经元中积累具有异常内部结构的碎片化线粒体。在 Parkin 缺陷小鼠中观察到与年龄相关的运动功能障碍和线粒体受损。以及在其 DA 神经元中积累具有异常内部结构的碎片化线粒体。在 Parkin 缺陷小鼠中观察到与年龄相关的运动功能障碍和线粒体受损。