Single-Cell Transcriptomics of Parkinson's Disease Human In Vitro Models Reveals Dopamine Neuron-Specific Stress Responses
Single-Cell Transcriptomics of Parkinson's Disease Human In Vitro Models Reveals Dopamine Neuron-Specific Stress Responses
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DOI：
10.1016/j.celrep.2020.108263
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发表时间：
2020-10-13
期刊：
影响因子：
8.8
通讯作者：
Metzakopian, Emmanouil
中科院分区：
文献类型：
--
作者：
Fernandes, Hugo J. R.;Patikas, Nikolaos;Metzakopian, Emmanouil
诱导多能干细胞 (iPSC) 衍生神经元的出现彻底改变了帕金森病 (PD) 研究，但单细胞转录组分析表明这些模型中尚未解决的细胞异质性。在这里，我们对人类 iPSC 衍生的多巴胺能神经元进行了最大规模的单细胞转录组研究，以阐明响应细胞毒性和遗传应激的基因表达动态。我们鉴定了具有不同转录特征和对压力不同敏感性的多种神经元亚型，突出了多巴胺体外模型中的细胞异质性。我们通过显示 PD GWAS 基因的稳健表达以及与死后成人黑质神经元的重叠来验证该疾病模型。重要的是，使用 FDA 批准的药物非洛地平可以改善压力特征。使用同基因 SNCA-A53T 突变体，我们发现了糖酵解、胆固醇代谢、突触信号传导和泛素蛋白酶体降解的扰动。总的来说，我们的研究揭示了人类多巴胺神经元中细胞类型特异性的扰动，这将进一步加深我们对帕金森病的理解，并对细胞替代疗法产生影响。
The advent of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized Parkinson's disease (PD) research, but single-cell transcriptomic analysis suggests unresolved cellular heterogeneity within these models. Here, we perform the largest single-cell transcriptomic study of human iPSC-derived dopaminergic neurons to elucidate gene expression dynamics in response to cytotoxic and genetic stressors. We identify multiple neuronal subtypes with transcriptionally distinct profiles and differential sensitivity to stress, highlighting cellular heterogeneity in dopamine in vitro models. We validate this disease model by showing robust expression of PD GWAS genes and overlap with postmortem adult substantia nigra neurons. Importantly, stress signatures are ameliorated using felodipine, an FDA-approved drug. Using isogenic SNCA-A53T mutants, we find perturbations in glycolysis, cholesterol metabolism, synaptic signaling, and ubiquitin-proteasomal degradation. Overall, our study reveals cell type-specific perturbations in human dopamine neurons, which will further our understanding of PD and have implications for cell replacement therapies.