Zeng Xiaomei, Han Zhifen, Chen Kehan, Zeng Peng, Tang Yidan, Li Lijuan
Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.
Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, China.
Parkinsons Dis. 2023 Dec 19;2023:5057778. doi: 10.1155/2023/5057778. eCollection 2023.
Parkinson's disease (PD) is a common neuron degenerative disease among the old, characterized by uncontrollable movements and an impaired posture. Although widely investigated on its pathology and treatment, the disease remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) has been applied to the area of PD, providing valuable data for related research. However, few works have taken deeper insights into the causes of neuron death and cell-cell interaction between the cell types in the brain. Our bioinformatics analyses revealed necroptosis-related genes (NRGs) enrichment in neuron degeneration and selecting the cells by NRGs levels showed two subtypes within the main degenerative cell types in the midbrain. NRG-low subtype was largely replaced by NRG-high subtype in the patients, indicating the striking change of cell state related to necroptosis in PD progression. Moreover, we carried out cell-cell interaction analyses between cell types and found that microglia (MG)'s interaction strength with glutamatergic neuron (GLU), GABAergic neuron (GABA), and dopaminergic neuron (DA) was significantly upregulated in PD. Also, MG show much stronger interaction with NRG-high subtypes and a stronger cell killing function in PD samples. Additionally, we identified CLDN11 as a novel interaction pattern specific to necroptosis neurons and MG. We also found LEF1 and TCF4 as key transcriptional regulators in neuron degeneration. These findings suggest that MG were significantly overactivated in PD patients to clear abnormal neurons, especially the NRG-high cells, explaining the neuron inflammation in PD. Our analyses provide insights into the causes of neuron death and inflammation in PD from single-cell resolution, which could be seriously considered in clinical trials.
帕金森病（PD）是老年人中常见的神经元退行性疾病，其特征为无法控制的运动和姿势受损。尽管对其病理和治疗进行了广泛研究，但该疾病仍未被完全理解。单细胞RNA测序（scRNA-seq）已应用于PD领域，为相关研究提供了有价值的数据。然而，很少有研究深入探讨神经元死亡的原因以及大脑中细胞类型之间的细胞间相互作用。我们的生物信息学分析揭示了坏死性凋亡相关基因（NRGs）在神经元变性中的富集，并且通过NRGs水平选择细胞显示中脑主要变性细胞类型内存在两种亚型。在患者中，NRG低亚型在很大程度上被NRG高亚型所取代，这表明在PD进展中与坏死性凋亡相关的细胞状态发生了显著变化。此外，我们对细胞类型之间进行了细胞间相互作用分析，发现小胶质细胞（MG）与谷氨酸能神经元（GLU）、γ-氨基丁酸能神经元（GABA）和多巴胺能神经元（DA）的相互作用强度在PD中显著上调。而且，在PD样本中，MG与NRG高亚型的相互作用更强且具有更强的细胞杀伤功能。此外，我们将CLDN11鉴定为坏死性凋亡神经元和MG特有的一种新型相互作用模式。我们还发现LEF1和TCF4是神经元变性中的关键转录调节因子。这些发现表明，PD患者中的MG被显著过度激活以清除异常神经元，尤其是NRG高的细胞，这解释了PD中的神经元炎症。我们的分析从单细胞分辨率深入了解了PD中神经元死亡和炎症的原因，这在临床试验中应予以认真考虑。
