Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.

中文翻译：

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多巴胺氧化介导帕金森氏病的线粒体和溶酶体功能障碍

帕金森氏病（PD）中的黑质多巴胺能神经退行性病变与线粒体和溶酶体功能障碍有关，但尚不清楚这些通路如何与人类神经元联系。在这里，我们研究了来自特发性和家族性PD患者的多巴胺能神经元。我们确定了时间依赖性病理级联，其始于线粒体氧化应激，导致氧化的多巴胺积累，并最终导致葡萄糖脑苷脂酶活性降低，溶酶体功能障碍和α-突触核蛋白积累。这种毒性级联反应是在人的PD神经元中观察到的，而在小鼠的PD神经元中观察不到，至少部分是由于多巴胺代谢的物种特异性差异。小鼠中脑神经元中多巴胺合成或α-突触核蛋白含量的增加概括了人类神经元中观察到的病理表型。因此，多巴胺氧化代表PD发病机理中的线粒体与溶酶体功能障碍之间的重要联系。