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Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases
O-GlcNAc is a common modification found on nuclear and cytoplasmic proteins. Determining the catalytic mechanism of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, enabled the creation of potent and selective inhibitors of this regulatory enzyme. Such inhibitors have served as im...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687168/ https://www.ncbi.nlm.nih.gov/pubmed/37918804 http://dx.doi.org/10.1016/j.jbc.2023.105411 |
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author | Pratt, Matthew R. Vocadlo, David J. |
author_facet | Pratt, Matthew R. Vocadlo, David J. |
author_sort | Pratt, Matthew R. |
collection | PubMed |
description | O-GlcNAc is a common modification found on nuclear and cytoplasmic proteins. Determining the catalytic mechanism of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, enabled the creation of potent and selective inhibitors of this regulatory enzyme. Such inhibitors have served as important tools in helping to uncover the cellular and organismal physiological roles of this modification. In addition, OGA inhibitors have been important for defining the augmentation of O-GlcNAc as a promising disease-modifying approach to combat several neurodegenerative diseases including both Alzheimer’s disease and Parkinson’s disease. These studies have led to development and optimization of OGA inhibitors for clinical application. These compounds have been shown to be well tolerated in early clinical studies and are steadily advancing into the clinic. Despite these advances, the mechanisms by which O-GlcNAc protects against these various types of neurodegeneration are a topic of continuing interest since improved insight may enable the creation of more targeted strategies to modulate O-GlcNAc for therapeutic benefit. Relevant pathways on which O-GlcNAc has been found to exert beneficial effects include autophagy, necroptosis, and processing of the amyloid precursor protein. More recently, the development and application of chemical methods enabling the synthesis of homogenous proteins have clarified the biochemical effects of O-GlcNAc on protein aggregation and uncovered new roles for O-GlcNAc in heat shock response. Here, we discuss the features of O-GlcNAc in neurodegenerative diseases, the application of inhibitors to identify the roles of this modification, and the biochemical effects of O-GlcNAc on proteins and pathways associated with neurodegeneration. |
format | Online Article Text |
id | pubmed-10687168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-106871682023-11-30 Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases Pratt, Matthew R. Vocadlo, David J. J Biol Chem JBC Reviews O-GlcNAc is a common modification found on nuclear and cytoplasmic proteins. Determining the catalytic mechanism of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, enabled the creation of potent and selective inhibitors of this regulatory enzyme. Such inhibitors have served as important tools in helping to uncover the cellular and organismal physiological roles of this modification. In addition, OGA inhibitors have been important for defining the augmentation of O-GlcNAc as a promising disease-modifying approach to combat several neurodegenerative diseases including both Alzheimer’s disease and Parkinson’s disease. These studies have led to development and optimization of OGA inhibitors for clinical application. These compounds have been shown to be well tolerated in early clinical studies and are steadily advancing into the clinic. Despite these advances, the mechanisms by which O-GlcNAc protects against these various types of neurodegeneration are a topic of continuing interest since improved insight may enable the creation of more targeted strategies to modulate O-GlcNAc for therapeutic benefit. Relevant pathways on which O-GlcNAc has been found to exert beneficial effects include autophagy, necroptosis, and processing of the amyloid precursor protein. More recently, the development and application of chemical methods enabling the synthesis of homogenous proteins have clarified the biochemical effects of O-GlcNAc on protein aggregation and uncovered new roles for O-GlcNAc in heat shock response. Here, we discuss the features of O-GlcNAc in neurodegenerative diseases, the application of inhibitors to identify the roles of this modification, and the biochemical effects of O-GlcNAc on proteins and pathways associated with neurodegeneration. American Society for Biochemistry and Molecular Biology 2023-10-31 /pmc/articles/PMC10687168/ /pubmed/37918804 http://dx.doi.org/10.1016/j.jbc.2023.105411 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | JBC Reviews Pratt, Matthew R. Vocadlo, David J. Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases |
title | Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases |
title_full | Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases |
title_fullStr | Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases |
title_full_unstemmed | Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases |
title_short | Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases |
title_sort | understanding and exploiting the roles of o-glcnac in neurodegenerative diseases |
topic | JBC Reviews |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687168/ https://www.ncbi.nlm.nih.gov/pubmed/37918804 http://dx.doi.org/10.1016/j.jbc.2023.105411 |
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