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Single-cell sequencing of the human midbrain reveals glial activation and a neuronal state specific to Parkinson's disease
medRxiv - Neurology Pub Date : 2020-09-30 , DOI: 10.1101/2020.09.28.20202812
Semra Smajic , Cesar Augusto Prada-Medina , Zied Landoulsi , Carola Dietrich , Javier Jarazo , Jana Henck , Saranya Balachandran , Sinthuja Pachchek , Christopher M Morris , Paul Antony , Bernd Timmermann , Sascha Sauer , Jens C Schwamborn , Patrick May , Anne Grunewald , Malte Spielmann

Parkinson's disease (PD) etiology is associated with genetic and environmental factors that lead to a loss of dopaminergic neurons. However, the functional interpretation of PD-associated risk variants and how other midbrain cells contribute to this neurodegenerative process are poorly understood. Here, we profiled >41,000 single-nuclei transcriptomes of postmortem midbrain tissue from 6 idiopathic PD (IPD) patients and 5 matched controls. We show that PD-risk variants are associated with glia- and neuron-specific gene expression patterns. Furthermore, Microglia and astrocytes presented IPD-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. IPD-microglia revealed a specific pro-inflammatory trajectory. Finally, we discovered a neuronal cell cluster exclusively present in IPD midbrains characterized by CADPS2 overexpression and a high proportion of cycling cells. We conclude that elevated CADPS2 expression is specific to dysfunctional dopaminergic neurons, which have lost their dopaminergic identity and unsuccessful attempt to re-enter the cell cycle.

中文翻译:

人类中脑的单细胞测序揭示了神经胶质激活和帕金森氏病特有的神经元状态

帕金森氏病(PD)的病因与导致多巴胺能神经元丧失的遗传和环境因素有关。然而,PD相关的风险变体的功能解释以及其他中脑细胞如何促进这种神经退行性过程了解甚少。在这里,我们剖析了来自6名特发性PD(IPD)患者和5名匹配对照的死后中脑组织的> 41,000个单核转录组。我们显示PD风险变异与胶质细胞和神经元特异性基因表达模式有关。此外,小胶质细胞和星形胶质细胞表现出IPD特异性细胞增殖和与未反应的蛋白质反应和细胞因子信号转导相关的基因失调。IPD小胶质细胞显示出特定的促炎轨迹。最后,我们发现仅存在于IPD中脑中的神经元细胞簇,其特征是CADPS2过表达和高比例的循环细胞。我们得出的结论是,升高的CADPS2表达特定于功能异常的多巴胺能神经元,后者失去了其多巴胺能的特性,并且未成功尝试重新进入细胞周期。
更新日期:2020-10-02
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