Graduate School of Education, Shandong Sport University, Jinan, Shandong 250102, China.
Xuzhou Clinical School, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China.
Brain Res Bull. 2024 Oct 15;217:111076. doi: 10.1016/j.brainresbull.2024.111076. Epub 2024 Sep 19.
In recent years, overwhelming evidence has emphasized the crucial role of inflammation in the pathogenesis of PD. However, the exact mechanisms by which inflammation damages dopaminergic neurons in PD are still unclear. Therefore, we generated a MPTP-induced PD mouse model and performed spatial transcriptomic sequencing to provide more insight into the process of PD development at specific brain regions. Our results indicate that the pathological changes of PD are mainly manifested in the midbrain, especially in the substantia nigra region, with significant reductions in oligodendrocytes and Agt-labeled astrocytes and an increase in Gfap-labeled astrocytes. Macrophages displayed an increasing trend in the PD environment, indicating a pattern of immune modulation induced by PD. Moreover, pathway analysis revealed significant impairments in ion migration ability, abnormal Ca channels, cAMP signaling, and synaptic damage in PD. Significant downregulation of Mt1 and Mt2 and upregulation of Atp1b2, Gpi1, and Cox6a1 in PD further underscored the occurrence of intense inflammation and immune alterations. On the basis of these findings, we have validated the significant accumulation of Ca in the midbrain tissue in the PD environment by measuring its content. Additionally, we have demonstrated a close association between the reduction of dopaminergic neurons, represented by the midbrain region, and ferroptosis by evaluating the iron content, malondialdehyde (MDA) levels, and the protein expression of GPX4 and TH in the tissue. We propose the hypothesis that PD-related inflammation and immune changes can induce neuronal and oligodendrocyte damage through the induction of ferroptosis, thereby further accelerating the progression of PD.
近年来，大量证据强调了炎症在 PD 发病机制中的关键作用。然而，炎症如何损害 PD 中的多巴胺能神经元的具体机制仍不清楚。因此，我们生成了一个 MPTP 诱导的 PD 小鼠模型，并进行了空间转录组测序，以提供对特定脑区 PD 发展过程的更深入了解。我们的结果表明，PD 的病理变化主要表现在中脑，特别是黑质区域，少突胶质细胞和 Agt 标记的星形胶质细胞明显减少，Gfap 标记的星形胶质细胞增加。PD 环境中的巨噬细胞呈增加趋势，表明 PD 诱导的免疫调节模式。此外，通路分析显示 PD 中离子迁移能力、异常 Ca 通道、cAMP 信号和突触损伤显著受损。Mt1 和 Mt2 的显著下调以及 Atp1b2、Gpi1 和 Cox6a1 的上调进一步强调了强烈的炎症和免疫改变的发生。基于这些发现，我们通过测量其含量，验证了 PD 环境中中脑组织中 Ca 的大量积累。此外，我们通过评估组织中铁含量、丙二醛 (MDA) 水平以及 GPX4 和 TH 的蛋白表达，证明了中脑区域代表的多巴胺能神经元减少与铁死亡之间的密切关联。我们提出假设，PD 相关的炎症和免疫变化可以通过诱导铁死亡来诱导神经元和少突胶质细胞损伤，从而进一步加速 PD 的进展。
