Burbulla Lena F, Song Pingping, Mazzulli Joseph R, Zampese Enrico, Wong Yvette C, Jeon Sohee, Santos David P, Blanz Judith, Obermaier Carolin D, Strojny Chelsee, Savas Jeffrey N, Kiskinis Evangelos, Zhuang Xiaoxi, Krüger Rejko, Surmeier D James, Krainc Dimitri
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129, USA.
Science. 2017 Sep 22;357(6357):1255-1261. doi: 10.1126/science.aam9080. Epub 2017 Sep 7.
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.
线粒体和溶酶体功能障碍与帕金森病（PD）中黑质多巴胺能神经元变性有关，但这些途径在人类神经元中如何联系尚不清楚。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。我们发现了一个时间依赖性的病理级联反应，始于线粒体氧化应激，导致氧化多巴胺积累，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。这种毒性级联反应在人类PD神经元中观察到，但在小鼠中未观察到，至少部分原因是多巴胺代谢存在物种特异性差异。增加小鼠中脑神经元中的多巴胺合成或α-突触核蛋白量可重现人类神经元中观察到的病理表型。因此，多巴胺氧化是PD发病机制中线粒体和溶酶体功能障碍之间的重要联系。
