Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University; No. 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University; No. 74 Zhongshan 2nd Road, Guangzhou 510080, China.
Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Organ Transplantation Institute of Sun Yat-sen University, Guangzhou 510630, China.
Neurobiol Dis. 2023 May;180:106105. doi: 10.1016/j.nbd.2023.106105. Epub 2023 Mar 26.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by the progressive loss of nigrostriatal dopaminergic neurons (DANs), involving the dysregulation of both neurons and glial cells. Cell type- and region-specific gene expression profiles can provide an effective source for revealing the mechanisms of PD. In this study, we adopted the RiboTag approach to obtain cell type (DAN, microglia, astrocytes)- and brain region (substantia nigra, caudate-putamen)-specific translatomes at an early stage in an MPTP-induced mouse model of PD. Through DAN-specific translatome analysis, the glycosphingolipid biosynthetic process was identified as a significantly downregulated pathway in the MPTP-treated mice. ST8Sia6, a key downregulated gene related to glycosphingolipid biosynthesis, was confirmed to be downregulated in nigral DANs from postmortem brains of patients with PD. Specific expression of ST8Sia6 in DANs exerts anti-inflammatory and neuroprotective effects in MPTP-treated mice. Through cell type (microglia vs. astrocyte) and brain region (substantia nigra vs. caudate-putamen) comparisons, nigral microglia showed the most intense immune responses. Microglia and astrocytes in the substantia nigra showed similar levels of activation in interferon-related pathways and interferon gamma (IFNG) was identified as the top upstream regulator in both cell types. This work highlights that the glycosphingolipid metabolism pathway in the DAN is involved in neuroinflammation and neurodegeneration in an MPTP mouse model of PD and provides a new data source for elucidating the pathogenesis of PD.
帕金森病（PD）是最常见的神经退行性运动障碍，其特征是黑质纹状体多巴胺能神经元（DAN）进行性丧失，涉及神经元和神经胶质细胞的失调。细胞类型和区域特异性基因表达谱可以为揭示 PD 的机制提供有效的来源。在这项研究中，我们采用了 RiboTag 方法，在 MPTP 诱导的 PD 小鼠模型的早期获得了细胞类型（DAN、小胶质细胞、星形胶质细胞）和脑区（黑质、尾壳核）特异性的翻译组。通过 DAN 特异性翻译组分析，鉴定出糖脂生物合成过程是 MPTP 处理的小鼠中显著下调的途径。ST8Sia6 是与糖脂生物合成相关的关键下调基因，被证实是 PD 患者死后黑质 DAN 中下调的基因。ST8Sia6 在 DAN 中的特异性表达在 MPTP 处理的小鼠中发挥抗炎和神经保护作用。通过细胞类型（小胶质细胞与星形胶质细胞）和脑区（黑质与尾壳核）的比较，黑质小胶质细胞表现出最强的免疫反应。黑质中的小胶质细胞和星形胶质细胞在干扰素相关途径中表现出相似的激活水平，干扰素γ（IFNG）被鉴定为这两种细胞类型的顶级上游调节剂。这项工作强调了 DAN 中的糖脂代谢途径参与了 MPTP 诱导的 PD 小鼠模型中的神经炎症和神经退行性变，并为阐明 PD 的发病机制提供了新的数据源。
