NOX4 exacerbates Parkinson's disease pathology by promoting neuronal ferroptosis and neuroinflammation.

IF 5.9 2区 医学 Q2 CELL BIOLOGY
Neural Regeneration Research Pub Date : 2025-07-01 Epub Date: 2024-07-10 DOI:10.4103/NRR.NRR-D-23-01265
Zhihao Lin, Changzhou Ying, Xiaoli Si, Naijia Xue, Yi Liu, Ran Zheng, Ying Chen, Jiali Pu, Baorong Zhang
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引用次数: 0

Abstract

JOURNAL/nrgr/04.03/01300535-202507000-00026/figure1/v/2024-09-09T124005Z/r/image-tiff Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta. Ferroptosis, a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation, plays a vital role in the death of dopaminergic neurons. However, the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated. NADPH oxidase 4 is related to oxidative stress, however, whether it regulates dopaminergic neuronal ferroptosis remains unknown. The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis, and if so, by what mechanism. We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model. NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons. Moreover, NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals. Mechanistically, we found that NADPH oxidase 4 interacted with activated protein kinase C α to prevent ferroptosis of dopaminergic neurons. Furthermore, by lowering the astrocytic lipocalin-2 expression, NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation. These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation, which contribute to dopaminergic neuron death, suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.

NOX4 通过促进神经元铁变态反应和神经炎症加剧了帕金森病的病理变化。
摘要:帕金森病主要是由黑质中多巴胺能神经元的丧失引起的。多巴胺能神经元的铁中毒是一种新型的调节性细胞死亡形式,其特点是铁积累和脂质过氧化,在多巴胺能神经元的死亡中起着至关重要的作用。然而,多巴胺能神经元铁中毒的分子机制尚未完全阐明。NADPH 氧化酶 4 与氧化应激有关,但它是否调控多巴胺能神经元的铁氧化作用仍不得而知。本研究的目的是确定 NADPH 氧化酶 4 是否参与了多巴胺能神经元的铁突变,如果是,参与的机制是什么。我们发现,在 l-甲基-4-苯基-l,2,3,6 四氢吡啶诱导的帕金森病模型中,转录调节因子活化转录因子 3 增加了多巴胺能神经元和星形胶质细胞中 NADPH 氧化酶 4 的表达。抑制 NADPH 氧化酶 4 可改善帕金森病模型动物的行为障碍,减少多巴胺能神经元的死亡。此外,抑制 NADPH 氧化酶 4 还能减少帕金森病模型动物黑质中的脂质过氧化和铁积累。从机理上讲,我们发现 NADPH 氧化酶 4 与活化的蛋白激酶 C α 相互作用,阻止了多巴胺能神经元的铁沉积。此外,通过降低星形胶质细胞脂钙蛋白-2的表达,NADPH氧化酶4抑制剂可减少l-甲基-4-苯基-1,2,3,6四氢吡啶诱导的神经炎症。这些研究结果表明,NADPH氧化酶4可促进多巴胺能神经元的铁变态反应和神经炎症,从而导致多巴胺能神经元死亡,这表明NADPH氧化酶4可能是帕金森病的治疗靶点。
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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来源期刊
Neural Regeneration Research
Neural Regeneration Research CELL BIOLOGY-NEUROSCIENCES
CiteScore
8.00
自引率
9.80%
发文量
515
审稿时长
1.0 months
期刊介绍: Neural Regeneration Research (NRR) is the Open Access journal specializing in neural regeneration and indexed by SCI-E and PubMed. The journal is committed to publishing articles on basic pathobiology of injury, repair and protection to the nervous system, while considering preclinical and clinical trials targeted at improving traumatically injuried patients and patients with neurodegenerative diseases.
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