Chen Yuanxin, Zhi Lianteng, Cui Shiquan, Wang Huaixin, Zeng Chenbo, Zhang Hui
Department of Physiology & Pharmacology, The University of Georgia, Athens, United States, 30602.
Department of Neuroscience, Thomas Jefferson University, Philadelphia, United States, 19107.
bioRxiv. 2025 Jun 17:2025.06.16.660029. doi: 10.1101/2025.06.16.660029.
Mitochondrial dysfunction and oxidative stress are central to Parkinson's disease (PD) pathogenesis, particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons. Using a BAC transgenic mouse model overexpressing human LRRK2-R1441G, we crossed these mice with TH-mito-roGFP mice, enabling mitochondria-targeted redox imaging in DA neurons. The two-photon imaging of acute brain slices from 3-, 6-, and 10-month-old mice revealed a progressive elevated oxidative stress in SNc DA neurons and their striatal projections, accompanied with reduced respiratory complex activity and decline in mitochondrial health. Spatial transcriptomics via GeoMx Digital Spatial Profiler identified molecular changes linked to dysregulated mitochondrial uncoupling protein function and calcium homeostasis. These findings demonstrate age-dependent mitochondrial dysfunction in LRRK2-mutant SNc DA neurons, highlighting calcium channels and uncoupling proteins as potential therapeutic targets to slow PD progression.
线粒体功能障碍和氧化应激是帕金森病（PD）发病机制的核心，尤其影响黑质致密部（SNc）多巴胺（DA）能神经元。在此，我们研究富含亮氨酸重复激酶2（LRRK2）中的R1441G突变如何影响中脑DA能神经元的线粒体功能，LRRK2是家族性和散发性PD的关键遗传因素。使用过表达人LRRK2-R1441G的BAC转基因小鼠模型，我们将这些小鼠与TH-线粒体-roGFP小鼠杂交，从而能够对DA能神经元进行线粒体靶向氧化还原成像。对3个月、6个月和10个月大小鼠的急性脑片进行双光子成像显示，SNc DA能神经元及其纹状体投射中的氧化应激逐渐升高，同时呼吸复合体活性降低，线粒体健康状况下降。通过GeoMx数字空间剖析仪进行的空间转录组学分析确定了与线粒体解偶联蛋白功能失调和钙稳态相关的分子变化。这些发现表明LRRK2突变的SNc DA能神经元中存在年龄依赖性线粒体功能障碍，突出了钙通道和解偶联蛋白作为减缓PD进展的潜在治疗靶点。
