State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Haikou, 570228, China.
Nat Commun. 2023 Nov 18;14(1):7497. doi: 10.1038/s41467-023-43213-2.
The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.
帕金森病（PD）中的退行性过程导致黑质纹状体系统中的多巴胺能神经元（DaNs）进行性丧失。解决神经元易感性的差异需要一个合适的 PD 模型，该模型与死后的人类标本相比，可控制 PD 发病机制中的环境和遗传差异。在这里，我们从 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病猕猴的黑质（SN）和纹状体（PT）中生成了 250,173 个细胞的高质量图谱，并与对照进行了比较。我们的灵长类帕金森病模型再现了自然 PD 中的重要病理特征，并提供了神经元易损性和抵抗性轴的无偏视图。我们确定了七个分子定义的黑质 DaN 亚型，这些亚型表现出脆弱性梯度，并通过荧光激活核分选得到了证实。神经元的弹性与 PD 抵抗性 DaNs 和谷氨酸能兴奋性神经元之间以及人类和非人类灵长类动物之间共同的 FOXP2 为中心的调节途径有关。我们还发现了与 SN 和 PT 的神经胶质细胞共同激活的免疫反应，表明黑质纹状体系统中同时激活了途径。我们的研究提供了一个独特的资源，可以了解神经元易感性与 PD 病理生理学之间的机制联系，并促进未来的生物标志物发现和靶向细胞治疗。
