The accumulation of Ca²⁺ and its subsequent increase in oxidative stress is proposed to be involved in selective dysfunctionality of dopaminergic neurons, the main cell type affected in Parkinson's disease. To test the in vivo impact of Ca²⁺ increment in dopaminergic neurons physiology, we downregulated the plasma membrane Ca²⁺ ATPase (PMCA), a pump that extrudes cytosolic Ca²⁺, by expressing PMCA^RNAi in Drosophila melanogaster dopaminergic neurons. In these animals, we observed major locomotor alterations paralleled to higher cytosolic Ca²⁺ and increased levels of oxidative stress in mitochondria. Interestingly, although no overt degeneration of dopaminergic neurons was observed, evidences of neuronal dysfunctionality were detected such as increases in presynaptic vesicles in dopaminergic neurons and in the levels of dopamine in the brain, as well as presence of toxic effects when PMCA was downregulated in the eye. Moreover, reduced PMCA levels were found in a Drosophila model of Parkinson's disease, Parkin knock-out, expanding the functional relevance of PMCA reduction to other Parkinson's disease-related models. In all, we have generated a new model to study motor abnormalities caused by increments in Ca²⁺ that lead to augmented oxidative stress in a dopaminergic environment, added to a rise in synaptic vesicles and dopamine levels.

中文翻译：

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多巴胺能神经元的质膜钙 ATP 酶下调改变黑腹果蝇的细胞生理学和运动行为

Ca ²⁺的积累及其随后氧化应激的增加被认为与多巴胺能神经元的选择性功能障碍有关，多巴胺能神经元是帕金森病中受影响的主要细胞类型。为了测试Ca ²⁺增加对多巴胺能神经元生理学的体内影响，我们通过在黑腹果蝇多巴胺能神经元中表达 PMCA ^RNAi来下调质膜 Ca ²⁺ ATPase (PMCA)，这是一种挤出胞质 Ca ²⁺的泵。在这些动物中，我们观察到与较高的细胞溶质 Ca ²⁺平行的主要运动改变和增加线粒体中的氧化应激水平。有趣的是，虽然没有观察到多巴胺能神经元的明显退化，但检测到神经元功能障碍的证据，例如多巴胺能神经元突触前囊泡和大脑中多巴胺水平的增加，以及当 PMCA 在眼睛。此外，在帕金森病的果蝇模型中发现 PMCA 水平降低，Parkin 敲除，将 PMCA 减少的功能相关性扩展到其他帕金森病相关模型。总之，我们生成了一个新模型来研究由 Ca ²⁺增加引起的运动异常 这会导致多巴胺能环境中的氧化应激增加，从而增加突触小泡和多巴胺水平。