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Protective Roles of O‐GlcNAc in Neurodegenerative Diseases
Author(s) -
Vocadlo David
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00054
Subject(s) - neurodegeneration , biochemistry , oxidative stress , glycosyltransferase , genetically modified mouse , cytosol , glycation , enzyme , glycobiology , biology , transgene , chemistry , microbiology and biotechnology , disease , gene , medicine , glycoprotein , receptor , glycan
O‐linked N‐acetylglucosamine (O‐GlcNAc) is an abundant form of protein O‐glycosylation found in the nucleus, cytoplasm, and mitochondria of all multicellular eukaryotes. This modification is found on several hundred proteins but is surprisingly regulated by only two enzymes; the glycosyltransferase O‐GlcNAc transferase (OGT) and the glycoside hydrolase O‐GlcNAcase (OGA). Because the substrate of OGT is derived from glucose, the levels of O‐GlcNAc within cells reflect environmental glucose availability. O‐GlcNAc has also emerged as part of a coordinated response to cellular stresses and levels of this modification increase markedly on exposure to diverse stresses ranging from heat shock to oxidative stress. These observations have stimulated interest in the potential protective roles of increased O‐GlcNAc in a range of tissues including in brain, where impaired nutrient utilization has been linked to various neurodegenerative diseases. Remarkably, brain permeable small molecule inhibitors of OGA have been shown to be surprisingly well tolerated in a range of animal models. Moreover, pharmacological agents that increase O‐GlcNAc levels in the brains of various transgenic models of Alzheimer Disease (AD) strikingly reduce the progression of disease pathology and neurodegeneration. While these effects have been shown to be remarkably reproducible, and OGA inhibitors have now been found to be generally well tolerated in early clinical trials, the mechanisms by which O‐GlcNAc protect against these pathologies and neurodegeneration remain less clear. Here we will discuss new advances in the biochemistry of OGA inhibitors, efforts to create improved inhibitors, and the protective effects of OGA in transgenic models of neurodegenerative diseases. Finally, we will discuss recent progress on various possible protective mechanisms by which increased O‐GlcNAc levels confer protection against various neurodegenerative diseases ranging from blockade of aggregation of toxic proteins to the induction of autophagy.