Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
Neuromolecular Med. 2017 Sep;19(2-3):322-344. doi: 10.1007/s12017-017-8448-8. Epub 2017 Jun 15.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha-synuclein monomer levels. Oxygen consumption was decreased by alpha-synuclein overexpression, but ATP levels did not decrease and ROS levels did not increase. Treatment with ferrous sulfate, a ROS generator, resulted in decreased oxygen consumption in both control and alpha-synuclein overexpressing cells. However, this treatment only decreased ATP levels and increased ROS production in the cells overexpressing alpha-synuclein. Similarly, paraquat, another ROS generator, decreased ATP levels in the alpha-synuclein overexpressing cells, but not in the control cells, further demonstrating how alpha-synuclein sensitized the cells to oxidative insult. Proteomic analysis yielded molecular insights into the cellular adaptations to alpha-synuclein overexpression, such as the increased abundance of many mitochondrial proteins. Many amino acids and citric acid cycle intermediates and their ester forms were individually supplemented to the cells with L-serine, L-proline, L-aspartate, or L-glutamine decreasing ROS production in oxidatively stressed alpha-synuclein overexpressing cells, while diethyl oxaloacetate or L-valine supplementation increased ATP levels. These results suggest that dietary supplementation with individual metabolites could yield bioenergetic improvements in PD patients to delay loss of dopaminergic neurons.
帕金森病（PD）是一种神经退行性疾病，其特征是α-突触核蛋白积累和大脑黑质（SN）区域多巴胺能神经元丧失。已经表明，α-突触核蛋白水平升高会导致线粒体电子传递链复合物 I 活性丧失，从而导致活性氧（ROS）产生增加。WT α-突触核蛋白在人 BE（2）-M17 神经母细胞瘤细胞中稳定过表达，导致α-突触核蛋白多聚体水平增加，但α-突触核蛋白单体水平没有增加。α-突触核蛋白过表达导致耗氧量降低，但 ATP 水平没有降低，ROS 水平也没有增加。用硫酸亚铁（ROS 生成剂）处理，在对照细胞和α-突触核蛋白过表达细胞中均导致耗氧量降低。然而，这种处理仅降低了α-突触核蛋白过表达细胞中的 ATP 水平并增加了 ROS 的产生。同样，百草枯（另一种 ROS 生成剂）降低了α-突触核蛋白过表达细胞中的 ATP 水平，但对照细胞没有，进一步证明了α-突触核蛋白如何使细胞对氧化损伤敏感。蛋白质组学分析为细胞对α-突触核蛋白过表达的适应提供了分子见解，例如许多线粒体蛋白的丰度增加。用 L-丝氨酸、L-脯氨酸、L-天冬氨酸或 L-谷氨酰胺分别向细胞中补充许多氨基酸和柠檬酸循环中间产物及其酯形式，可降低氧化应激下α-突触核蛋白过表达细胞中的 ROS 产生，而二乙氧代戊二酸或 L-缬氨酸的补充则增加了 ATP 水平。这些结果表明，用个体代谢物进行饮食补充可能会改善 PD 患者的生物能量，从而延缓多巴胺能神经元的丧失。
