NFKB1 对 CD200R1 表达的调控及其在帕金森病中的潜在作用。

The regulation of NFKB1 on CD200R1 expression and their potential roles in Parkinson's disease.

机构信息

Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Department of Aging, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

出版信息

J Neuroinflammation. 2024 Sep 18;21(1):229. doi: 10.1186/s12974-024-03231-3.

DOI:10.1186/s12974-024-03231-3

PMID:39294682

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11409543/

Abstract

BACKGROUND

Overactivated microglia are a key contributor to Parkinson's disease (PD) by inducing neuroinflammation. CD200R1, a membrane glycoprotein mainly found on microglia, is crucial for maintaining quiescence with its dysregulation linked to microglia's abnormal activation. We and other groups have reported a decline in CD200R1 levels in several neurological disorders including PD. However, the mechanism regulating CD200R1 expression and the specific reasons for its reduction in PD remain largely unexplored. Given the pivotal role of transcription factors in gene expression, this study aimed to elucidate the transcriptional regulation of CD200R1 and its implications in PD.

METHODS

The CD200R1 promoter core region was identified via luciferase assays. Potential transcription factors were predicted using the UCSC ChIP-seq database and JASPAR. NFKB1 binding to the CD200R1 core promoter was substantiated through electrophoretic mobility shift and chromatin immunoprecipitation assays. Knocking-down or overexpressing NFKB1 validated its regulatory effect on CD200R1. Correlation between decreased CD200R1 and deficient NFKB1 was studied using Genotype-Tissue Expression database. The clinical samples of the peripheral blood mononuclear cells were acquired from 44 PD patients (mean age 64.13 ± 9.78, 43.2% male, median Hoehn-Yahr stage 1.77) and 45 controls (mean age 64.70 ± 9.41, 52.1% male). NFKB1 knockout mice were utilized to study the impact of NFKB1 on CD200R1 expression and to assess their roles in PD pathophysiology.

RESULTS

The study identified the CD200R1 core promoter region, located 482 to 146 bp upstream of its translation initiation site, was directly regulated by NFKB1. Significant correlation between NFKB1 and CD200R1 expression was observed in human PMBCs. Both NFKB1 and CD200R1 were significantly decreased in PD patient samples. Furthermore, NFKB1-/- mice exhibited exacerbated microglia activation and dopaminergic neuron loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment.

CONCLUSION

Our study identified that NFKB1 served as a direct regulator of CD200R1. Reduced NFKB1 played a critical role in CD200R1 dysregulation and subsequent microglia overactivation in PD. These findings provide evidence that targeting the NFKB1-CD200R1 axis would be a novel therapeutic strategy for PD.

摘要

背景

过度激活的小胶质细胞通过诱导神经炎症成为帕金森病（PD）的关键致病因素。CD200R1 是一种主要存在于小胶质细胞上的膜糖蛋白，对于维持小胶质细胞的静止状态至关重要，其失调与小胶质细胞的异常激活有关。我们和其他研究小组已经报道，在包括 PD 在内的几种神经退行性疾病中，CD200R1 水平下降。然而，调节 CD200R1 表达的机制以及 PD 中其减少的具体原因在很大程度上仍未得到探索。鉴于转录因子在基因表达中的关键作用，本研究旨在阐明 CD200R1 的转录调控及其在 PD 中的意义。

方法

通过荧光素酶检测鉴定 CD200R1 启动子核心区域。使用 UCSC ChIP-seq 数据库和 JASPAR 预测潜在的转录因子。通过电泳迁移率变动和染色质免疫沉淀检测证实 NFKB1 与 CD200R1 核心启动子的结合。敲低或过表达 NFKB1 验证了其对 CD200R1 的调节作用。使用 Genotype-Tissue Expression 数据库研究 CD200R1 减少与 NFKB1 缺乏之间的相关性。从 44 名 PD 患者（平均年龄 64.13±9.78 岁，43.2%为男性，中位 Hoehn-Yahr 分期 1.77）和 45 名对照者（平均年龄 64.70±9.41 岁，52.1%为男性）获得外周血单核细胞的临床样本。使用 NFKB1 敲除小鼠研究 NFKB1 对 CD200R1 表达的影响，并评估其在 PD 病理生理学中的作用。

结果

本研究确定了位于其翻译起始位点上游 482 至 146bp 的 CD200R1 核心启动子区域，直接受到 NFKB1 的调控。在人 PMBCs 中观察到 NFKB1 与 CD200R1 表达之间存在显著相关性。PD 患者样本中 NFKB1 和 CD200R1 均显著减少。此外，NFKB1-/- 小鼠在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理后表现出更严重的小胶质细胞激活和多巴胺能神经元丢失。