Wakatsuki Shuji, Araki Toshiyuki
Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Neural Regen Res. 2023 Apr;18(4):746-749. doi: 10.4103/1673-5374.354509.
Neurite degeneration, a major component of many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, is not part of the typical apoptosis signaling mechanism, but rather it appears that a self-destructive process is in action. Oxidative stress is a well-known inducer of neurodegenerative pathways: neuronal cell death and neurite degeneration. Although oxidative stress exerts cytotoxic effects leading to neuronal loss, the pathogenic mechanisms and precise signaling pathways by which oxidative stress causes neurite degeneration have remained entirely unknown. We previously reported that reactive oxygen species generated by NADPH oxidases induce activation of the E3 ubiquitin ligase ZNRF1 in neurons, which promotes neurite degeneration. In this process, the phosphorylation of an NADPH oxidase subunit p47-phox at the 345 serine residue serves as an important checkpoint to initiate the ZNRF1-dependent neurite degeneration. Evidence provides new insights into the mechanism of reactive oxygen species-mediated neurodegeneration. In this review, we focus specifically on reactive oxygen species-induced neurite degeneration by highlighting a phosphorylation-dependent regulation of the molecular interaction between ZNRF1 and the NADPH oxidase complex.
神经突退化是许多神经退行性疾病（如帕金森病、阿尔茨海默病和肌萎缩侧索硬化症）的主要组成部分，它并非典型细胞凋亡信号机制的一部分，而是似乎有一种自我破坏过程在起作用。氧化应激是神经退行性通路（神经元细胞死亡和神经突退化）的一个众所周知的诱导因素。尽管氧化应激会产生细胞毒性作用导致神经元丧失，但氧化应激导致神经突退化的致病机制和精确信号通路仍完全未知。我们之前报道过，NADPH氧化酶产生的活性氧会诱导神经元中E3泛素连接酶ZNRF1的激活，从而促进神经突退化。在此过程中，NADPH氧化酶亚基p47-phox在丝氨酸345残基处的磷酸化是启动ZNRF1依赖性神经突退化的一个重要检查点。有证据为活性氧介导的神经退行性变机制提供了新的见解。在这篇综述中，我们通过强调ZNRF1与NADPH氧化酶复合物之间分子相互作用的磷酸化依赖性调节，特别关注活性氧诱导的神经突退化。
