Li Huiying, Wang Hongquan, Zhang Ling, Wang Manshi, Li Yanfeng
Department of Neurology, Beijing Aerospace General Hospital, Beijing, China.
Department of Neurology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, China.
Front Neurosci. 2021 May 28;15:647266. doi: 10.3389/fnins.2021.647266. eCollection 2021.
Aggregation and neurotoxicity of the presynaptic protein α-synuclein and the progressive loss of nigral dopaminergic neurons are believed to be the key hallmarks of Parkinson's disease (PD). A53T mutant α-synuclein causes early onset PD and more severe manifestations. A growing body of evidence shows that misfolding or deposition of α-synuclein is linked to the maintenance of mitochondrial dynamics, which has been proven to play an important role in the pathogenesis of PD. It has been observed that Dl-3-n-butylphthalide (NBP) may be safe and effective in improving the non-tremor-dominant PD. However, the potential mechanism remains unclear. This study aimed to investigate whether NBP could decrease the loss of dopaminergic neurons and α-synuclein deposition and explore its possible neuroprotective mechanisms.
A total of 20 twelve-month-old human A53T α-synuclein transgenic mice and 10 matched adult C57BL/6 mice were included in the study; 10 adult C57BL/6 mice were selected as the control group and administered with saline (0.2 ml daily for 14 days); 20 human A53T α-synuclein transgenic mice were randomly divided into A53T group (treated in the same manner as in the control group) and A53T + NBP group (treated with NBP 0.2 ml daily for 14 days). Several markers of mitochondrial fission and fusion and mitophagy were determined, and the behavioral, olfactory, and cognitive symptoms were assessed as well.
In the present study, it was observed that the A53T-α-synuclein PD mice exhibited anxiety-like behavioral disturbance, impairment of coordination ability, memory deficits, and olfactory dysfunction, loss of dopaminergic neurons, and α-synuclein accumulation. Meanwhile, the mitofusin 1 expression was significantly decreased, and the mitochondrial number and dynamin-related protein 1, Parkin, and LC3 levels were increased. The detected levels of all markers were reversed by NBP treatment, and the mitochondrial morphology was partially recovered.
In the present study, a valuable neuropharmacological role of NBP has been established in the A53T-α-synuclein PD mouse model. Possible neuroprotective mechanisms might be that NBP is involved in the maintenance of mitochondrial dynamics including mitochondrial fission and fusion and clearance of damaged mitochondria. It is essential to perform further experiments to shed light on the precise mechanisms of NBP on mitochondrial homeostasis.
突触前蛋白α-突触核蛋白的聚集和神经毒性以及黑质多巴胺能神经元的进行性丧失被认为是帕金森病（PD）的关键标志。A53T突变型α-突触核蛋白会导致早发性PD且症状更严重。越来越多的证据表明，α-突触核蛋白的错误折叠或沉积与线粒体动力学的维持有关，这已被证明在PD的发病机制中起重要作用。据观察，丁苯酞（NBP）可能对改善非震颤为主型PD安全有效。然而，其潜在机制仍不清楚。本研究旨在探讨NBP是否能减少多巴胺能神经元的损失和α-突触核蛋白沉积，并探索其可能的神经保护机制。
本研究共纳入20只12月龄的人A53Tα-突触核蛋白转基因小鼠和10只匹配的成年C57BL/6小鼠；选取10只成年C57BL/6小鼠作为对照组，给予生理盐水（每天0.2 ml，共14天）；将20只人A53Tα-突触核蛋白转基因小鼠随机分为A53T组（处理方式与对照组相同）和A53T + NBP组（每天给予NBP 0.2 ml，共14天）。测定了线粒体分裂、融合和线粒体自噬的几个标志物，并评估了行为、嗅觉和认知症状。
在本研究中，观察到A53T-α-突触核蛋白PD小鼠表现出焦虑样行为障碍、协调能力受损、记忆缺陷和嗅觉功能障碍、多巴胺能神经元丧失以及α-突触核蛋白积累。同时，线粒体融合蛋白1表达显著降低，线粒体数量以及动力相关蛋白1、帕金蛋白和微管相关蛋白1轻链3水平升高。NBP治疗可逆转所有检测标志物的水平，并使线粒体形态部分恢复。
在本研究中，已在A53T-α-突触核蛋白PD小鼠模型中确立了NBP有价值的神经药理学作用。可能的神经保护机制可能是NBP参与了线粒体动力学的维持，包括线粒体的分裂和融合以及受损线粒体的清除。有必要进行进一步实验以阐明NBP对线粒体稳态的确切机制。
