O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy
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 metabol...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-05-01
|
| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2023.1137847/full |
| _version_ | 1797830467519512576 |
|---|---|
| author | Hsueh-Fu Wu Hsueh-Fu Wu Chia-Wei Huang Chia-Wei Huang Jennifer Art Jennifer Art Hong-Xiang Liu Gerald W. Hart Gerald W. Hart Nadja Zeltner Nadja Zeltner Nadja Zeltner |
| author_facet | Hsueh-Fu Wu Hsueh-Fu Wu Chia-Wei Huang Chia-Wei Huang Jennifer Art Jennifer Art Hong-Xiang Liu Gerald W. Hart Gerald W. Hart Nadja Zeltner Nadja Zeltner Nadja Zeltner |
| author_sort | Hsueh-Fu Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T13:36:33Z |
| format | Article |
| id | doaj.art-d0edf94f88504e9db6a15704a368b4d2 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-09T13:36:33Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-d0edf94f88504e9db6a15704a368b4d22023-05-09T08:48:38ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-05-011710.3389/fnins.2023.11378471137847O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathyHsueh-Fu Wu0Hsueh-Fu Wu1Chia-Wei Huang2Chia-Wei Huang3Jennifer Art4Jennifer Art5Hong-Xiang Liu6Gerald W. Hart7Gerald W. Hart8Nadja Zeltner9Nadja Zeltner10Nadja Zeltner11Center for Molecular Medicine, University of Georgia, Athens, GA, United StatesDepartment of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United StatesDepartment of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United StatesComplex Carbohydrate Research Center, University of Georgia, Athens, GA, United StatesCenter for Molecular Medicine, University of Georgia, Athens, GA, United StatesBiomedical and Translational Sciences Institute, Neuroscience Program, University of Georgia, Athens, GA, United StatesRegenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, United StatesDepartment of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United StatesComplex Carbohydrate Research Center, University of Georgia, Athens, GA, United StatesCenter for Molecular Medicine, University of Georgia, Athens, GA, United StatesDepartment of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United StatesDepartment of Cellular Biology, University of Georgia, Athens, GA, United StatesO-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.https://www.frontiersin.org/articles/10.3389/fnins.2023.1137847/fullO-GlcNAcylationperipheral nervous systemautonomic nervous systemsympathetic neuronhuman pluripotent stem cellsdiabetes |
| spellingShingle | Hsueh-Fu Wu Hsueh-Fu Wu Chia-Wei Huang Chia-Wei Huang Jennifer Art Jennifer Art Hong-Xiang Liu Gerald W. Hart Gerald W. Hart Nadja Zeltner Nadja Zeltner Nadja Zeltner O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy Frontiers in Neuroscience O-GlcNAcylation peripheral nervous system autonomic nervous system sympathetic neuron human pluripotent stem cells diabetes |
| title | O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy |
| title_full | O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy |
| title_fullStr | O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy |
| title_full_unstemmed | O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy |
| title_short | O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy |
| title_sort | o glcnacylation is crucial for sympathetic neuron development maintenance functionality and contributes to peripheral neuropathy |
| topic | O-GlcNAcylation peripheral nervous system autonomic nervous system sympathetic neuron human pluripotent stem cells diabetes |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2023.1137847/full |
| work_keys_str_mv | AT hsuehfuwu oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT hsuehfuwu oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT chiaweihuang oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT chiaweihuang oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT jenniferart oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT jenniferart oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT hongxiangliu oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT geraldwhart oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT geraldwhart oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT nadjazeltner oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT nadjazeltner oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy AT nadjazeltner oglcnacylationiscrucialforsympatheticneurondevelopmentmaintenancefunctionalityandcontributestoperipheralneuropathy |