Table 1.
O-GlcNAcylation status in aging and neurodegenerative diseases.
| Condition | Species | Brain region (cell type)/molecular target | O-GlcNAc status | Phenotype | References |
|---|---|---|---|---|---|
| Aging | Mouse | Whole-brain | Decreased | - | 48 |
| Hippocampus | Decreased | Impaired cognitive function | 44 | ||
| Hippocampus (neural stem cell) | Decreased | Impaired neurogenesis, gliogenesis, and hippocampal-dependent learning | 47 | ||
| Whole-body | Increased (by GlcN supplementation) | Extended lifespan | 51 | ||
| C. elegans | Whole-body | Increased (by gfat-1 gain-of-function mutation or supplementation of GlcNAc) | Extended lifespan | 50 | |
| Increased (by GlcN supplementation) | 51 | ||||
| Alzheimer’s disease (animal model) | Human | Frontal cortex, Brodmann area 7, inferior parietal lobule | Decreased | - | 57,61–63 |
| Mouse | Brain, cervical spinal cord/tau | Increased (by pharmacological OGA inhibition) | Reduced pathological tau phosphorylation, attenuated neurofibrillary tangles, and neuronal death | 59 | |
| Amyloid-beta (Aβ) | Increased (by pharmacological OGA inhibition or genetic upregulation of OGA expression) | Reduction of Aβ by attenuated γ-secretase activity, reduction of activated microglia and astrocyte, reduced neuronal death, recovery of impaired memory function | 63,69 | ||
| Rat | Hippocampus/tau | Increased (by pharmacological OGA inhibition) | Reduced tau phosphorylation | 66 | |
| Cultured cells | PC-12 cells | Increased (by pharmacological OGA inhibition) | Reduced tau phosphorylation | 66 | |
| Huntington’s disease (animal model) | Mouse | Cortex/nucleoporin (NUP) | Decreased | Mislocalized NUPs | 80 |
| Cultured cells | Primary cortical neurons/huntingtin | Increased (by pharmacological OGA inhibition) | Reduced cell death | 80 | |
| Neuro2A cells | Decreased (by genetic OGA expression) | Reduced mutant huntingtin aggregation and cell death | 76 | ||
| Amyotrophic lateral sclerosis (animal model) | Mouse | Ventral horn of the spinal cord | Decreased | Reduced number of motor neurons | 85 |
| Spinal cord | Decreased | Excessive ROS, motor neuron death | 91 | ||
| Rat | Spinal cord/neurofilament | Decreased | Neurofilament loss | 89 | |
| Cultured cells | SH-SY5Y cell/TDP-43 | Increased (by genetic upregulation of OGT expression or by GlcNAc treatment) | Attenuated aggregation of abnormal TDP-43 and cellular toxicity | 94 | |
| Parkinson’s disease (animal model) | Mouse | α-synuclein | Increased (by genetic and pharmacological enhancement of O-GlcNAc) | Reduced α-synuclein aggregation, reduced dopaminergic neuron death, recovered dopamine release, and motor function | 32 |
| Cultured cells | SH-SY5Y cell, hippocampal neuron, SK-N-SH neuroblastoma cells/α-synuclein | Increased (by site-specific mutation or pharmacological upregulation) | Reduced α-synuclein aggregation, reduced cell death, less toxicity, reduced α-synuclein preformed fibril (PFF) uptake | 106,107,109 |