Wang Jianli, Geng Ting, Yao Xiaomei, Liu Yiming
Department of Neurology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Lixia District, Jinan, 250012, Shandong, China.
Department of Geriatrics, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250102, Shandong, China.
Mol Cell Biochem. 2025 Apr 3. doi: 10.1007/s11010-025-05265-4.
Growth differentiation Factor 15 (GDF15) plays an important role in the innate immune response. However, whether GDF15 could regulate Parkinson's disease (PD) remains unknown. In this study, we explored the function and underlying molecular mechanisms of GDF15 in PD. The protein and mRNA expressions were examined applying immunofluorescence staining, Western blot and qRT-PCR. Ferrous iron content was also assessed using an iron assay kit. The effect of GDF15 knockdown on mitochondrial membrane potential, ROS level, intracellular Fe level and mitochondrial permeability transition pore opening in PD cell model was evaluated utilizing JC-1 staining, DCFH-DA fluorescent probe, ferro orange staining and calcein AM + Co quencher staining. GDF15 was upregulated in the substantia nigra and striatum of PD mice and MPP-caused SH-SY5Y cells. GDF15 knockdown aggravated parkinsonian symptoms in PD mice. Moreover, GDF15 knockdown aggravated dopamine neuronal damage, and promoted ferroptosis and inflammation in PD in vivo and in vitro. Besides, GDF15 knockdown could activate cGAS-STING pathway in vivo and in vitro PD model. We also found that the treatment of RU.521 could reverse the effect of GDF15 knockdown on dopamine neuronal damage, inflammation and ferroptosis in MPP-induced SH-SY5Y cells. Similarly, the treatment of SR-717 could reverse the effect of GDF15 overexpression on dopamine neuronal damage, inflammation and ferroptosis in MPP-induced SH-SY5Y cells. The results of this study demonstrated that GDF15 could attenuate dopamine neuronal damage, and inhibit ferroptosis and inflammation in PD via suppressing cGAS-STING pathway activation.
生长分化因子15（GDF15）在先天免疫反应中起重要作用。然而，GDF15是否能调节帕金森病（PD）仍不清楚。在本研究中，我们探讨了GDF15在PD中的功能及潜在分子机制。应用免疫荧光染色、蛋白质印迹法和qRT-PCR检测蛋白质和mRNA表达。还使用铁检测试剂盒评估亚铁含量。利用JC-1染色、DCFH-DA荧光探针、铁橙染色和钙黄绿素AM+Co淬灭剂染色评估GDF15敲低对PD细胞模型中线粒体膜电位、ROS水平、细胞内铁水平和线粒体通透性转换孔开放的影响。GDF15在PD小鼠的黑质和纹状体以及MPP诱导的SH-SY5Y细胞中上调。GDF15敲低加重了PD小鼠的帕金森症状。此外，GDF15敲低加重了多巴胺神经元损伤，并在体内和体外促进了PD中的铁死亡和炎症。此外，GDF15敲低可在体内和体外PD模型中激活cGAS-STING途径。我们还发现，RU.521处理可逆转GDF15敲低对MPP诱导的SH-SY5Y细胞中多巴胺神经元损伤、炎症和铁死亡的影响。同样，SR-717处理可逆转GDF15过表达对MPP诱导的SH-SY5Y细胞中多巴胺神经元损伤、炎症和铁死亡的影响。本研究结果表明GDF15可减轻多巴胺神经元损伤，并通过抑制cGAS-STING途径激活来抑制PD中的铁死亡和炎症。
