Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Int J Mol Sci. 2021 Jan 9;22(2):601. doi: 10.3390/ijms22020601.
Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson's disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.
线粒体功能障碍是帕金森病 (PD) 发病机制中的一个关键事件。越来越多的证据表明，线粒体动力学和质量控制的紊乱在 PD 中线粒体功能障碍中发挥重要作用。我们之前的研究表明，MPP 在体外诱导线粒体碎片化。在这项研究中，我们旨在评估通过过表达 Mfn2 来阻止 MPTP 诱导的线粒体碎片化是否能在体内提供神经保护作用。我们发现，MPTP 处理后，野生型同窝对照小鼠的黑质 (SN) 中多巴胺能神经元的显著丢失几乎完全被过表达 Mfn2 (hMfn2 小鼠) 所阻断。MPTP 给药引起的纹状体多巴胺神经元纤维和多巴胺水平的急剧减少在 hMfn2 小鼠中也部分受到抑制。MPTP 诱导的 SN 和纹状体中的氧化应激和炎症反应在 hMfn2 小鼠中显著减轻。hMfn2 小鼠也阻断了由 MPTP 引起的运动功能障碍。总的来说，我们的工作表明，通过过表达 Mfn2 恢复线粒体动力学可以防止基于 MPTP 的 PD 小鼠模型中的神经元毒性，这支持了作为 PD 治疗的潜在治疗靶点的线粒体动力学的调节。
