O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy

Frontiers in Neuroscience

Neuroscience

Jennifer Art¹  Hsueh-Fu Wu²  Nadja Zeltner³  Chia-Wei Huang⁴  Gerald W. Hart⁴  Hong-Xiang Liu⁵ 

[1] Center for Molecular Medicine, University of Georgia, Athens, GA, United States;Biomedical and Translational Sciences Institute, Neuroscience Program, University of Georgia, Athens, GA, United States;Center for Molecular Medicine, University of Georgia, Athens, GA, United States;Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United States;Center for Molecular Medicine, University of Georgia, Athens, GA, United States;Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United States;Department of Cellular Biology, University of Georgia, Athens, GA, United States;Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United States;Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States;Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, United States;

关键词: O-GlcNAcylation;    peripheral nervous system;    autonomic nervous system;    sympathetic neuron;    human pluripotent stem cells;    diabetes;    hyperglycemia;    peripheral neuropathy;   

DOI  :  10.3389/fnins.2023.1137847

 received in 2023-01-04, accepted in 2023-04-12,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Wu, Huang, Art, Liu, Hart and Zeltner.