Jiang Chengcheng, Li Yangyang, Duan Kexin, Zhan Tingting, Chen Zilong, Wang Yongxue, Zhao Rui, Ma Caiyun, Guo Yu, Liu Changqing
Anhui Provincial Center for Neural Regeneration Technology and New Medical Materials Engineering Research, Bengbu Medical University, Bengbu 233000, China.
School of Life Sciences, Bengbu Medical University, Bengbu 233000, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2024 Dec 20;44(12):2359-2366. doi: 10.12122/j.issn.1673-4254.2024.12.11.
To investigate the role of mitochondrial autophagy disorder caused by deletion of E3 ubiquitin ligase Parkin in neuroinflammation in a mouse model of MPTP-induced Parkinson's disease (PD).
Wild-type (WT) male C57BL/6 mice and Parkin mice were given intraperitoneal injections with MPTP or PBS for 5 consecutive days, and the changes in motor behaviors of the mice were observed using open field test. The effects of Parkin deletion on PD development and neuroinflammation were evaluated using immunofluorescence and Western blotting. The changes of the PINK 1/Parkin signaling pathway in the midbrain substantia nigra of the mice were examined to explore the molecular mechanism of Parkin-mediated regulation of mitochondrial autophagy and its effect on neuroinflammation in PD mice.
Compared with their WT counterparts, the Parkin mice with MPTP injections exhibited significant impairment of motor function with decreased TH neurons, increased α-synuclein (α-syn) accumulation, and increased numbers of GFAP and I-ba1 cells in the midbrain substantia nigra. Parkin deletion obviously affected PINK1/Parkin-mediated mitochondrial autophagy to result in significantly increased mtDNA and upregulated expressions of STING and NLRP3 inflammatosomes in the midbrain substantia nigra of MPTP-treated transgenic mice.
Parkin deletion causes mitochondrial autophagy disorder to accelerate PD progression and exacerbates neuroinflammation in mice by affecting the PINK1/Parkin signaling pathway, suggesting the important role of Parkin in early pathogenesis of PD.
在MPTP诱导的帕金森病（PD）小鼠模型中，研究E3泛素连接酶Parkin缺失所致线粒体自噬障碍在神经炎症中的作用。
将野生型（WT）雄性C57BL/6小鼠和Parkin基因敲除小鼠连续5天腹腔注射MPTP或PBS，采用旷场试验观察小鼠运动行为的变化。运用免疫荧光和蛋白质免疫印迹法评估Parkin缺失对PD发展和神经炎症的影响。检测小鼠中脑黑质中PINK 1/Parkin信号通路的变化，以探讨Parkin介导的线粒体自噬调节的分子机制及其对PD小鼠神经炎症的影响。
与野生型小鼠相比，注射MPTP的Parkin基因敲除小鼠表现出明显的运动功能障碍，中脑黑质中TH神经元减少，α-突触核蛋白（α-syn）积累增加，GFAP和I-ba1细胞数量增多。Parkin缺失明显影响PINK1/Parkin介导的线粒体自噬，导致MPTP处理的转基因小鼠中脑黑质中mtDNA显著增加，STING和NLRP3炎性小体的表达上调。
Parkin缺失导致线粒体自噬障碍，通过影响PINK1/Parkin信号通路加速小鼠PD进展并加重神经炎症，提示Parkin在PD早期发病机制中起重要作用。
