Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg.
Department of Life Science and Medicine (DLSM), University of Luxembourg, 4362 Belvaux, Luxembourg.
Cell Rep. 2021 Oct 19;37(3):109864. doi: 10.1016/j.celrep.2021.109864.
Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases. We investigate the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson's disease (PD). We monitor the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons. Using high-throughput image analyses and single-cell RNA sequencing, we observe that the PD-associated LRRK2-G2019S mutation alters the initial phase of neuronal differentiation by accelerating cell-cycle exit with a concomitant increase in cell death. We identify the NESC-specific core regulatory circuit and a molecular mechanism underlying the observed phenotypes. The expression of NR2F1, a key transcription factor involved in neurogenesis, decreases in LRRK2-G2019S NESCs, neurons, and midbrain organoids compared to controls. We also observe accelerated dopaminergic differentiation in vivo in NR2F1-deficient mouse embryos. This suggests a pathogenic mechanism involving the LRRK2-G2019S mutation, where the dynamics of dopaminergic differentiation are modified via NR2F1.
越来越多的证据表明，神经发育异常可能导致易患神经退行性疾病。我们在帕金森病（PD）模型中研究多巴胺能神经元的发育异常。我们监测人源患者特异性神经上皮干细胞（NESCs）向多巴胺能神经元的分化。通过高通量图像分析和单细胞 RNA 测序，我们观察到 PD 相关的 LRRK2-G2019S 突变通过加速细胞周期退出并伴随细胞死亡增加来改变神经元分化的初始阶段。我们确定了 NESC 特异性核心调控回路和观察到的表型的分子机制。与对照组相比，LRRK2-G2019S NESCs、神经元和中脑类器官中参与神经发生的关键转录因子 NR2F1 的表达降低。我们还观察到 NR2F1 缺陷型小鼠胚胎中多巴胺能分化的加速。这表明存在一种涉及 LRRK2-G2019S 突变的致病机制，其中通过 NR2F1 来修饰多巴胺能分化的动力学。
