O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy.
O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy.
复制标题
DOI：
10.3389/fnins.2023.1137847
复制
发表时间：
2023
影响因子：
4.3
通讯作者：
Zeltner, Nadja
中科院分区：
文献类型：
--
作者：
Wu, Hsueh-Fu;Huang, Chia-Wei;Art, Jennifer;Liu, Hong-Xiang;Hart, Gerald W.;Zeltner, Nadja
关键词：
O-GlcNAcylation 是一种翻译后修饰 (PTM)，可调节多种细胞功能，并与多种器官的多种代谢疾病相关。交感神经系统（SNS）是自主神经系统的传出部分，调节体内几乎所有器官的新陈代谢。 SNS 的发育和功能在多大程度上受到 O-GlcNAcylation 的影响，以及这种调节如何导致疾病状态下的交感神经元 (symN) 相关神经病变，目前仍不清楚。在这里，我们使用基于人类多能干细胞 (hPSC) 的 symN 分化范例评估了 symN 发育各个阶段的蛋白质 O-GlcNAcNA 酰化水平。我们发现 O-GlcNAc 酰化的药理破坏会损害 hPSC 衍生符号的生长和存活。在模拟高血糖的高葡萄糖条件下，hPSC 衍生的符号过度活跃，其再生能力受损，这类似于糖尿病患者和动物模型中的典型神经元缺陷。利用这种交感神经病模型，我们发现高葡萄糖下 symN 中的 O-GlcNAc 酰化增加，从而导致多动症。 O-GlcNAc 酰化的药理学抑制可挽救高葡萄糖诱导的 symN 过度活跃和细胞应激。该框架首次深入了解 O-GlcNAc 酰化在健康和患病人类症状中的作用，并可用作治疗研究的平台。
O-GlcNAcylation is a post-translational modification (PTM) that regulates a wide range of cellular functions and has been associated with multiple metabolic diseases in various organs. The sympathetic nervous system (SNS) is the efferent portion of the autonomic nervous system that regulates metabolism of almost all organs in the body. How much the development and functionality of the SNS are influenced by O-GlcNAcylation, as well as how such regulation could contribute to sympathetic neuron (symN)-related neuropathy in diseased states, remains unknown. Here, we assessed the level of protein O-GlcNAcylation at various stages of symN development, using a human pluripotent stem cell (hPSC)-based symN differentiation paradigm. We found that pharmacological disruption of O-GlcNAcylation impaired both the growth and survival of hPSC-derived symNs. In the high glucose condition that mimics hyperglycemia, hPSC-derived symNs were hyperactive, and their regenerative capacity was impaired, which resembled typical neuronal defects in patients and animal models of diabetes mellitus. Using this model of sympathetic neuropathy, we discovered that O-GlcNAcylation increased in symNs under high glucose, which lead to hyperactivity. Pharmacological inhibition of O-GlcNAcylation rescued high glucose-induced symN hyperactivity and cell stress. This framework provides the first insight into the roles of O-GlcNAcylation in both healthy and diseased human symNs and may be used as a platform for therapeutic studies.
登录
查看更多内容
影响因子：
7.7
作者：
Frith TJ;Granata I;Wind M;Stout E;Thompson O;Neumann K;Stavish D;Heath PR;Ortmann D;Hackland JO;Anastassiadis K;Gouti M;Briscoe J;Wilson V;Johnson SL;Placzek M;Guarracino MR;Andrews PW;Tsakiridis A
通讯作者：
Tsakiridis A
DOI：
10.1042/bcj20200609
发表时间：
2021-07-30
期刊：
The Biochemical journal
影响因子：
--
作者：
Balana AT;Pratt MR
通讯作者：
Pratt MR
DOI：
10.1016/j.cjca.2020.03.003
发表时间：
2020-05
期刊：
The Canadian journal of cardiology
影响因子：
--
作者：
DeLalio LJ;Sved AF;Stocker SD
通讯作者：
Stocker SD
影响因子：
20.1
作者：
Hegyi B;Fasoli A;Ko CY;Van BW;Alim CC;Shen EY;Ciccozzi MM;Tapa S;Ripplinger CM;Erickson JR;Bossuyt J;Bers DM
通讯作者：
Bers DM
影响因子：
5.2
作者：
Chan, Jun-Wei;Teo, Adrian K. K.
通讯作者：
Teo, Adrian K. K.