University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
Inserm UMR S-1172 Team "Early stages of Parkinson's Disease", 1 Place de Verdun, 59006, Lille, France.
Mol Neurodegener. 2017 Nov 13;12(1):84. doi: 10.1186/s13024-017-0225-5.
Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD.
帕金森病（PD）是一种进行性运动神经退行性疾病，与大脑黑质中多巴胺能神经元的丧失有关。氧化应激是一种由于氧化剂和抗氧化剂状态失衡而发生的情况，被认为在多巴胺能神经毒性中起重要作用。烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶是多亚基酶复合物，其主要功能是产生活性氧。已经报道 PD 患者大脑中 NADPH 氧化酶催化亚基 Nox1、Nox2 和 Nox4 的免疫反应性增加。此外，NADPH 氧化酶的敲除或基因失活在该疾病的实验模型中发挥神经保护作用并减少病理学的有害方面。然而，NADPH 氧化酶与被认为有助于神经元死亡的生物学过程之间的联系尚不清楚。
本综述全面总结了我们目前对神经元、小胶质细胞和星形胶质细胞中 NADPH 氧化酶的表达和生理功能及其在 PD 中的病理生理作用的理解。它总结了支持小胶质细胞和神经元 NADPH 氧化酶在与 PD 相关的细胞紊乱（如神经炎症、α-突触核蛋白积累、线粒体和突触功能障碍或自噬-溶酶体系统中断）中的作用的发现。此外，本综述强调了 NADPH 氧化酶酶活性所必需的不同步骤，并指出了为开发用于 PD 的有效 NADPH 氧化酶抑制剂而需要克服的主要障碍。
