Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan 528000, China; NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Pharmacy, Nanfang hospital, Southern Medical University, Guangzhou 510515, China.
Neuroscience. 2024 Nov 12;560:109-119. doi: 10.1016/j.neuroscience.2024.09.033. Epub 2024 Sep 19.
Parkinson's disease (PD) is the second most common neurodegenerative disorder whose etiology remains unknown. The immune system has been implicated in hallmarks of PD including aggregation of α-synuclein and death of dopaminergic neurons in the substantia nigra. As a core regulator of immune response and inflammation, liver X receptors (LXRs) have been shown to have protective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. With two isoforms of LXRs (LXRα and LXRβ) expressed in the brain, their roles and distributions in this tissue remain largely unexplored. Here, we used MPTP to mimic symptoms and biomedical changes seen in PD in LXRα and wild-type mice to investigate the role of LXRα in the etiology and progression of PD. We found that MPTP is unable to induce motor deficits, anxiety-like behavior in LXRα mice, which has been seen in WT mice. Gene ontology analysis of RNA sequencing revealed that knockout of LXRα led to enrichment of the process, including immune response and inflammation in the midbrain. In addition, MPTP did not lead to dopaminergic neuron death in the striatum and substantia nigra in LXRα mice, the basal GFAP protein level, and pro-inflammatory cytokines were elevated in LXRα mice. Lastly, the microglia activation and astrogliosis caused by MPTP intoxication we found in WT mice were abolished in LXRα mice. To sum up, we conclude that LXRα is a critical regulator in MPTP intoxication and may play a unique role in astrogliosis seen in the neuroinflammation of PD.
帕金森病（PD）是第二常见的神经退行性疾病，其病因仍不清楚。免疫系统与 PD 的特征有关，包括α-突触核蛋白的聚集和黑质中多巴胺能神经元的死亡。作为免疫反应和炎症的核心调节剂，肝 X 受体（LXRs）已被证明在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中具有保护作用。大脑中表达有两种 LXR 同工型（LXRα和 LXRβ），它们在该组织中的作用和分布在很大程度上仍未得到探索。在这里，我们使用 MPTP 模拟 PD 中所见的症状和生物医学变化，在 LXRα 和野生型小鼠中研究 LXRα 在 PD 的病因和进展中的作用。我们发现，MPTP 无法诱导 LXRα 小鼠的运动缺陷和焦虑样行为，而在 WT 小鼠中则观察到这些症状。RNA 测序的基因本体分析表明，LXRα 的敲除导致中脑过程的富集，包括免疫反应和炎症。此外，MPTP 不会导致 LXRα 小鼠纹状体和黑质中的多巴胺能神经元死亡，LXRα 小鼠的基底 GFAP 蛋白水平和促炎细胞因子升高。最后，我们发现，在 WT 小鼠中，MPTP 中毒引起的小胶质细胞激活和星形胶质细胞增生在 LXRα 小鼠中被消除。总之，我们得出结论，LXRα 是 MPTP 中毒的关键调节剂，在 PD 神经炎症中的星形胶质细胞增生中可能发挥独特作用。
