Deficiency of N-glycanase 1 perturbs neurogenesis and cerebral development modeled by human organoids.
Deficiency of N-glycanase 1 perturbs neurogenesis and cerebral development modeled by human organoids.
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DOI：
10.1038/s41419-022-04693-0
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发表时间：
2022-03-24
影响因子：
9
通讯作者：
Wang YC
中科院分区：
文献类型：
--
作者：
Lin VJT;Hu J;Zolekar A;Salick MR;Mittal P;Bird JT;Hoffmann P;Kaykas A;Byrum SD;Wang YC
n -聚糖酶1 （N-glycanase 1, NGLY1）是一种将错误折叠的糖蛋白去糖基化以进行降解的酶，其突变可导致患者的NGLY1缺乏，并导致其多器官胎儿发育异常，包括小头畸形和其他神经系统疾病。利用人类胚胎干细胞（hESCs）和诱导多能干细胞（hiPSCs）发育的脑类器官（COs），我们研究了NGLY1功能障碍如何干扰早期大脑发育。虽然NGLY1缺失对未分化细胞的影响有限，但由NGLY1缺失的hESCs发育的COs显示satb2阳性上层神经元的形成缺陷，以及对维持放射状胶质至关重要的STAT3和HES1信号的衰减。大量和单细胞转录组学分析显示，在ngly1缺陷COs中，神经元过早分化伴随着分泌因子和转录因子的下调，包括TTR、IGFBP2和ID4。NGLY1功能障碍也会在体内CO移植中失调ID4并增强神经元分化。缺乏ngly1的CO细胞更容易受到多种应激源的影响；用重组TTR处理缺陷细胞降低了它们对蛋白酶体失活的易感性，可能是通过lrp2介导的MAPK信号激活。表达NGLY1导致NGLY1缺乏症患者hiPSCs培养的CO细胞中IGFBP2和ID4上调。此外，重组IGFBP2处理可增强ID4表达、STAT3信号传导和ngly1缺陷CO细胞的增殖。总的来说，我们的发现表明，应激反应和神经前体分化失调是ngly1缺乏个体中观察到的大脑异常的基础。
Mutations in N-glycanase 1 (NGLY1), which deglycosylates misfolded glycoproteins for degradation, can cause NGLY1 deficiency in patients and their abnormal fetal development in multiple organs, including microcephaly and other neurological disorders. Using cerebral organoids (COs) developed from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), we investigate how NGLY1 dysfunction disturbs early brain development. While NGLY1 loss had limited impact on the undifferentiated cells, COs developed from NGLY1-deficient hESCs showed defective formation of SATB2-positive upper-layer neurons, and attenuation of STAT3 and HES1 signaling critical for sustaining radial glia. Bulk and single-cell transcriptomic analysis revealed premature neuronal differentiation accompanied by downregulation of secreted and transcription factors, including TTR, IGFBP2, and ID4 in NGLY1-deficient COs. NGLY1 malfunction also dysregulated ID4 and enhanced neuronal differentiation in CO transplants developed in vivo. NGLY1-deficient CO cells were more vulnerable to multiple stressors; treating the deficient cells with recombinant TTR reduced their susceptibility to stress from proteasome inactivation, likely through LRP2-mediated activation of MAPK signaling. Expressing NGLY1 led to IGFBP2 and ID4 upregulation in CO cells developed from NGLY1-deficiency patient’s hiPSCs. In addition, treatment with recombinant IGFBP2 enhanced ID4 expression, STAT3 signaling, and proliferation of NGLY1-deficient CO cells. Overall, our discoveries suggest that dysregulation of stress responses and neural precursor differentiation underlies the brain abnormalities observed in NGLY1-deficient individuals.
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DOI：
10.1038/s41580-018-0001-6
发表时间：
2018-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
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通讯作者：
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影响因子：
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