靶向髓过氧化物酶以减轻 X-遗传性肌张力障碍性帕金森病的神经炎症

IF 4.8 1区 医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-11-05 DOI:10.1111/cns.70109
Tiziana Petrozziello, Negin Jalali Motlagh, Ranee Zara B. Monsanto, Dan Lei, Micaela G. Murcar, Ellen B. Penney, D. Cristopher Bragg, Cara Fernandez-Cerado, G. Paul Legarda, Michelle Sy, Edwin Muñoz, Mark C. Ang, Cid Czarina E. Diesta, Can Zhang, Rudolph E. Tanzi, Irfan A. Qureshi, John W. Chen, Ghazaleh Sadri-Vakili
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引用次数: 0

摘要

目的:X-连锁肌张力障碍性帕金森病(XDP)是一种在菲律宾流行的神经退行性疾病,虽然该病的基因位点已被明确,但导致神经元缺失的确切机制尚未完全清楚。最近,我们证实了 XDP 死后前额叶皮层(PFC)中髓过氧化物酶(MPO)水平的升高,这表明炎症在 XDP 发病机制中扮演了重要角色。因此,我们假设抑制 MPO 可为 XDP 提供一种治疗策略:方法:使用MPO活化荧光剂(MAFA)测量人死后脑前皮质中MPO的活性。结果:在抑制 MPO 后,测量了源自 XDP 的成纤维细胞和 SH-SY5Y 细胞中的活性氧(ROS)和 MPO 活性:结果:MPO 活性在 XDP PFC 中明显增加。此外,用死后 XDP PFC 处理细胞系会导致 ROS 水平明显增加。为了确定 MPO 活性的增加是否会导致 ROS 的增加,从 XDP 全氟碳化物中免疫去除了 MPO 含量,结果 SH-SY5Y 细胞中的 ROS 明显减少。同样,用一种强效的选择性 MPO 抑制剂--vediperstat 处理 XDP 衍生成纤维细胞和经 XDP PFC 处理的 SH-SY5Y 细胞时,ROS 都会显著减少:总之,我们的研究结果表明,MPO 抑制剂可减轻氧化应激,并可能为 XDP 治疗提供一种新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Targeting Myeloperoxidase to Reduce Neuroinflammation in X-Linked Dystonia Parkinsonism

Aims

Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP.

Methods

MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition.

Results

MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells.

Conclusions

Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment.

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来源期刊
CNS Neuroscience & Therapeutics
CNS Neuroscience & Therapeutics 医学-神经科学
CiteScore
7.30
自引率
12.70%
发文量
240
审稿时长
2 months
期刊介绍: CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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