Zhang Bohan, Song Chengyuan, Tang Xiao, Tian Min, Liu Yuqian, Yan Zhuoran, Duan Ruonan, Liu Yiming
Department of Neurology, Qilu Hospital, Shandong University, Jinan, China.
Front Cell Dev Biol. 2024 Jul 10;12:1422746. doi: 10.3389/fcell.2024.1422746. eCollection 2024.
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, and type 2 diabetes (T2DM) and PD are influenced by common genetic and environmental factors. Mitochondrial dysfunction and inflammation are common pathogenic mechanisms of both diseases. However, the close association between PD and T2DM and the specific relationship between them are not yet clear. This study aimed to reveal the specific connection between the two diseases by establishing a mouse model of comorbid PD and T2DM, as well as a Bv2 cell model.
C57BL/6 mouse were used to construct a model of PD with T2DM using streptozotocin and rotenone, while Bv2 cells were used to simulate the microenvironment of PD and T2DM using rotenone and palmitate. Behavioral tests were conducted to assess any differences in motor and cognitive functions in mouse. Immunohistochemistry was used to analyze the number of dopaminergic neurons in the substantia nigra region of mouse. Western blotting was used to detect the expression levels of TH, P-NFκB, NFκB, Cyclic GMP-AMP synthase (cGAS), and Stimulator of interferon genes (STING) proteins in the substantia nigra region of mouse and Bv2 cells. qRT-PCR was used to analyze the expression levels of IL1β, IL6, and TNF-α. Seahorse technology was used to assess mitochondrial function in Bv2 cells.
T2DM exacerbated the motor and cognitive symptoms in mouse with PD. This effect may be mediated by disrupting mitochondrial function in microglial cells, leading to damaged mtDNA leakage into the cytoplasm, subsequently activating the cGAS-STING pathway and downstream P-NFκB/NFκB proteins, triggering an inflammatory response in microglial cells. Microglial cells release inflammatory factors such as IL1β, IL6, and TNF-α, exacerbating neuronal damage caused by PD.
Our study results suggest that T2DM may exacerbate the progression of PD by damaging mitochondrial function, and activating microglial cell inflammation. The detrimental effects on Parkinson's disease may be achieved through the activating of the cGAS-STING protein pathway.
帕金森病（PD）是世界上第二常见的神经退行性疾病，2型糖尿病（T2DM）和PD受共同的遗传和环境因素影响。线粒体功能障碍和炎症是这两种疾病常见的致病机制。然而，PD与T2DM之间的密切关联及其具体关系尚不清楚。本研究旨在通过建立PD和T2DM共病小鼠模型以及Bv2细胞模型，揭示这两种疾病之间的具体联系。
采用C57BL/6小鼠，使用链脲佐菌素和鱼藤酮构建PD合并T2DM模型，而Bv2细胞则使用鱼藤酮和棕榈酸模拟PD和T2DM的微环境。进行行为测试以评估小鼠运动和认知功能的差异。免疫组织化学用于分析小鼠黑质区域多巴胺能神经元的数量。蛋白质印迹法用于检测小鼠黑质区域和Bv2细胞中酪氨酸羟化酶（TH）、磷酸化核因子κB（P-NFκB）、核因子κB（NFκB）、环鸟苷酸-腺苷酸合成酶（cGAS）和干扰素基因刺激因子（STING）蛋白的表达水平。实时定量聚合酶链反应（qRT-PCR）用于分析白细胞介素1β（IL1β）、白细胞介素6（IL6）和肿瘤坏死因子-α（TNF-α）的表达水平。采用海马技术评估Bv2细胞的线粒体功能。
T2DM加剧了PD小鼠的运动和认知症状。这种作用可能是通过破坏小胶质细胞的线粒体功能介导的，导致受损的线粒体DNA泄漏到细胞质中，随后激活cGAS-STING途径和下游的P-NFκB/NFκB蛋白，引发小胶质细胞的炎症反应。小胶质细胞释放IL1β、IL6和TNF-α等炎症因子，加剧了PD引起的神经元损伤。
我们的研究结果表明，T2DM可能通过损害线粒体功能和激活小胶质细胞炎症来加剧PD的进展。对帕金森病的有害影响可能是通过激活cGAS-STING蛋白途径实现的。
