Zhang Sen, Yan Min, Jiang Xing, Liu Youhan, Ma Wen, Ding Ling, Lu Zhimin, Luo Ying, Tian Xuewen, Wang Qinglu
College of Graduate Education, Shandong Sport University, Jinan, China.
Department of Clinical laboratory, Zibo Central Hospital, Zibo, China.
NPJ Parkinsons Dis. 2025 May 23;11(1):136. doi: 10.1038/s41531-025-00995-0.
Parkinson's disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca. Additionally, we demonstrated a significant reduction in the number of DA neurons in the SN region and a notable activation of ferroptosis, alongside a significant decrease in the antioxidant pathway NRF2/SLC7A11/GPX4. In summary, our data elucidate that ferroptosis in the midbrain SN region preferentially occurs in astrocytes under the dysregulation of oligodendrocytes, leading to ferroptosis in DA neurons. Thus, our study highlights the crucial role of oligodendrocyte-astrocyte crosstalk in driving neuronal inactivation and inflammatory expansion in PD.
帕金森病（PD）作为一种神经退行性疾病，其主要特征是中枢神经系统受损，伴有星形胶质细胞功能障碍和铁死亡激活。最近的研究表明，少突胶质细胞在PD患者大脑中也表现出功能异常，并参与铁死亡过程。然而，尚不清楚少突胶质细胞与星形胶质细胞之间是否存在相互作用以及它们如何诱导神经元铁死亡。在这里，我们采用单核测序和空间转录组学来表征PD环境中少突胶质细胞与星形胶质细胞之间的细胞间通讯网络。其中，星形胶质细胞是FGF（成纤维细胞生长因子）信号通路中少突胶质细胞发送信号的主要接收者。在PD中，通讯强度减弱，涉及FGF1和FGF9及其受体FGFR1、FGFR2和FGFR3。随后，我们进一步验证了PD小鼠少突胶质细胞和星形胶质细胞内线粒体氧化磷酸化过程的显著激活，并且星形胶质细胞可能还涉及Mt1和Ca的相互作用。此外，我们证明黑质区域多巴胺能神经元数量显著减少，铁死亡明显激活，同时抗氧化途径NRF2/SLC7A11/GPX4显著降低。总之，我们的数据表明，在少突胶质细胞失调的情况下，中脑黑质区域的铁死亡优先发生在星形胶质细胞中，导致多巴胺能神经元发生铁死亡。因此，我们的研究强调了少突胶质细胞 - 星形胶质细胞串扰在驱动PD神经元失活和炎症扩展中的关键作用。
