Sean M. Healey & AMG Center for ALS at Mass General, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Radiology, Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA.
CNS Neurosci Ther. 2024 Nov;30(11):e70109. doi: 10.1111/cns.70109.
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.
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.
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.
Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment.
虽然 X 连锁肌张力障碍帕金森病（XDP）的遗传基因座，这种神经退行性疾病在菲律宾流行，已经得到很好的描述，但导致神经元丧失的确切机制尚不完全清楚。最近，我们发现在 XDP 的死后前额叶皮层（PFC）中髓过氧化物酶（MPO）水平升高，这表明炎症在 XDP 的发病机制中起作用。因此，我们假设抑制 MPO 可能为 XDP 提供一种治疗策略。
使用 MPO 激活荧光剂（MAFA）测量人死后 PFC 中的 MPO 活性。在 XDP 衍生的成纤维细胞和 SH-SY5Y 细胞中，测量 MPO 抑制后活性氧（ROS）和 MPO 活性。
MPO 活性在 XDP PFC 中显著增加。此外，用死后 XDP PFC 处理细胞系会导致 ROS 水平显著升高。为了确定 MPO 活性的增加是否导致 ROS 的增加，我们从 XDP PFC 中免疫耗竭 MPO 含量，这导致 SH-SY5Y 细胞中的 ROS 显著减少。一致地，用 verdiperstat 治疗，一种有效的、选择性的 MPO 抑制剂，显著降低了 XDP 衍生的成纤维细胞和 XDP PFC 处理的 SH-SY5Y 细胞中的 ROS。
总的来说，我们的结果表明，MPO 抑制减轻氧化应激，并可能为 XDP 治疗提供一种新的治疗策略。
