Ma Zhuoran, Xu Yan, Lian Piaopiao, Wu Yi, Liu Ke, Zhang Zhaoyuan, Tang Zhicheng, Yang Xiaoman, Cao Xuebing
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430000, China.
Neurosci Bull. 2025 Jun;41(6):951-969. doi: 10.1007/s12264-024-01323-x. Epub 2024 Nov 28.
Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.
抑郁症（Dep）是帕金森病（PD）最常见的伴随症状之一，但目前缺乏帕金森病伴发抑郁症（PD-Dep）发生的详细病理证据。目前，使用传统药物干预来治疗这两种病症的症状仍然是一项艰巨的任务。在本研究中，我们发现PD-Dep大鼠内侧前额叶皮质（mPFC）中细胞外信号调节激酶（ERK）的激活受损、转录和翻译水平降低以及脑源性神经营养因子（BDNF）的表达减少。我们证明，α-突触核蛋白（pS129）的异常磷酸化导致原肌球蛋白相关激酶B型受体（TrkB）滞留在神经元细胞膜上，从而导致BDNF/TrkB信号功能障碍。我们选择SEW2871作为改善剂来上调ERK磷酸化。结果显示，PD-Dep大鼠的帕金森病和抑郁症行为表现有所改善。此外，pS129的减少伴随着PD-Dep大鼠mPFC中BDNF/ERK信号环功能的恢复。
