Wu Hao, Zhang Zhen-Hua, Zhou Ping, Sui Xin, Liu Xi, Sun Yi, Zhao Xin, Pu Xiao-Ping
National Key Research Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Antioxidants (Basel). 2024 Sep 30;13(10):1183. doi: 10.3390/antiox13101183.
Degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain are the main pathological changes in Parkinson's disease (PD); however, the mechanism underlying the selective vulnerability of specific neuronal populations in PD remains unclear. Here, we used single-cell RNA sequencing to identify seven cell clusters, including oligodendrocytes, neurons, astrocytes, oligodendrocyte progenitor cells, microglia, synapse-rich cells (SRCs), and endothelial cells, in the substantia nigra of a rotenone-induced rat model of PD based on marker genes and functional definitions. We found that SRCs were a previously unidentified cell subtype, and the tight interactions between SRCs and other cell populations can be improved by icaritin, which is a flavonoid extracted from Maxim. and exerts anti-neuroinflammatory, antioxidant, and immune-improving effects in PD. We also demonstrated that icaritin bound with transcription factors of SRCs, and icaritin application modulated synaptic characterization of SRCs, neuroinflammation, oxidative stress, and survival of dopaminergic neurons, and improved abnormal energy metabolism, amino acid metabolism, and phospholipase D metabolism of astrocytes in the substantia nigra of rats with PD. Moreover, icaritin supplementation also promotes the recovery of the physiological homeostasis of the other cell clusters to delay the pathogenesis of PD. These data uncovered previously unknown cellular diversity in a rat model of Parkinson's disease and provide insights into the promising therapeutic potential of icaritin in PD.
中脑黑质中多巴胺能神经元的变性和死亡是帕金森病（PD）的主要病理变化；然而，PD中特定神经元群体选择性易损性的潜在机制仍不清楚。在这里，我们基于标记基因和功能定义，使用单细胞RNA测序在鱼藤酮诱导的PD大鼠模型的黑质中鉴定出七个细胞簇，包括少突胶质细胞、神经元、星形胶质细胞、少突胶质细胞前体细胞、小胶质细胞、富含突触的细胞（SRCs）和内皮细胞。我们发现SRCs是一种先前未被识别的细胞亚型，淫羊藿素（一种从淫羊藿中提取的黄酮类化合物）可以改善SRCs与其他细胞群体之间的紧密相互作用，淫羊藿素在PD中具有抗神经炎症、抗氧化和改善免疫的作用。我们还证明淫羊藿素与SRCs的转录因子结合，应用淫羊藿素可调节SRCs的突触特征、神经炎症、氧化应激和多巴胺能神经元的存活，并改善PD大鼠黑质中星形胶质细胞的异常能量代谢、氨基酸代谢和磷脂酶D代谢。此外，补充淫羊藿素还可促进其他细胞簇生理稳态的恢复，以延缓PD的发病机制。这些数据揭示了帕金森病大鼠模型中以前未知的细胞多样性，并为淫羊藿素在PD中的潜在治疗前景提供了见解。
