帕金森病(PD)是最常见的神经退行性疾病。由激活的小胶质细胞介导的神经炎症和中脑多巴胺能(DA)神经元的凋亡是其主要病理表现。已观察到富含亮氨酸的重复蛋白激酶2(LRRK2)激酶在神经炎症期间增加表达,然而,LRRK2对小胶质细胞活化的影响尚不清楚。在这项研究中,我们已经建立了脂多糖(LPS)处理的BV2细胞和1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)模型,用于体内和体外研究。我们的体内数据表明,LRRK2可以通过调节铁凋亡和激活核因子-κB来促进小胶质细胞的激活。抑制LRRK2表达有效抑制LPS诱导的促炎细胞因子,促进神经保护因子的分泌。重要的是,通过共同过表达LRRK2和谷胱甘肽过氧化物酶4(GPX4),我们确定Xc-GSH-GPX4系统是LRRK2介导的小胶质细胞铁性凋亡和炎症反应的关键组成部分.使用小胶质细胞培养上清液(MCS)转移模型,我们发现抑制LRRK2或下调BV2细胞的铁凋亡可阻止SH-SY5Y细胞凋亡。此外,我们观察到LRRK2和P-P65在中脑的大量表达,在MPTP诱导的PD模型中升高,随着小胶质细胞的激活。用PF-06447475抑制LRRK2和P-P65表达减弱了MPTP处理的小鼠的黑质纹状体致密部分中的小胶质细胞活化。根据我们的发现,很明显,LRRK2通过调节系统Xc-GSH-GPX4通路在PD发病过程中促进神经炎症反应中起关键作用。一起来看,我们的数据突出了靶向LRRK2通过铁性凋亡调节PD神经炎症反应的潜在研究和治疗价值.
Parkinson\'s disease (PD) is the most prevalent neurodegenerative disorder. Neuroinflammation mediated by activated microglia and apoptosis of dopaminergic (DA) neurons in the midbrain are its primary pathological manifestations. Leucine-rich repeat protein kinase 2 (LRRK2) kinase has been observed to increase expression during neuroinflammation, however, the effect of
LRRK2 on microglia activation remains poorly understood. In this study, we have established lipopolysaccharide (LPS) treated BV2 cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models for both in vivo and in vitro investigation. Our data in vivo reveal that LRRK2 can promote microglia activation by regulating ferroptosis and activating nuclear factor-κB. Inhibition of
LRRK2 expression effectively suppressed the LPS-induced pro-inflammatory cytokines and facilitated the secretion of neuroprotective factors. Importantly, by co-overexpressing
LRRK2 and glutathione peroxidase 4 (GPX4), we identified the system Xc-GSH-GPX4 pathway as a crucial component in
LRRK2-mediated microglial ferroptosis and inflammatory responses. Using a microglial culture supernatant (MCS) transfer model, we found that inhibiting LRRK2 or downregulating ferroptosis in BV2 cells prevented SH-SY5Y cell apoptosis. Additionally, we observed abundant expression of
LRRK2 and P-P65 in the midbrain, which was elevated in the MPTP-induced PD model, along with microglia activation. LRRK2 and P-P65 expression inhibition with PF-06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP-treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc-GSH-GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis.