O-linked β-N-acetylglucosamine (O-GlcNAc) is ubiquitous in the human body and is particularly abundant in the brain. Various proteins commonly found in synapses are glycosylated with O-GlcNAc. O-GlcNAc Glycosylation is a dynamic, inducible post-translational modification that adds O-GlcNAc to serine or threonine (Ser/Thr) residues in many proteins. This modification occurs at various cellular locations and tightly regulates cellular processes such as transcription, protein homeostasis, stress response, autophagy, and metabolism. The dynamic cycle of O-GlcNAc glycosylation is regulated only by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT catalyzes the addition of GlcNAc from uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl groups of Ser/Thr residues of nucleoplasmic proteins to form β-O-glycosidic bonds. While OGA removes protein modifications. Although OGT is ubiquitously expressed, it is particularly abundant in neurons. OGT is involved in specialized neuronal processes, including activity-dependent transcription and long-term repression by regulating the cAMP response element-binding protein (CREB) and AMPA receptor GluA2 subunits, respectively. Changed and aberrant O-GlcNAcylation is frequently observed in neurodegenerative diseases, cancer, cardiac hypertrophy, and type II diabetes. Therefore, O-GlcNAcylation is not only involved in maintaining normal cellular functions but also involved in the pathological process of human diseases.
Fig.1 O-GlcNAcylation and its regulation of various cellular processes. (Lee, et al, 2021)
Disorders of Protein O-Glycosylation lead to specific glycosylation disease. Modulation of O-GlcNAc glycosylation in the brain has been reported to change synaptic and neuronal function. O-GlcNAc glycosylation is present on proteins associated with neurodegenerative diseases, such as α-synuclein, amyloid precursor protein, and tau protein. Changes in brain O-GlcNAcylation are associated with many neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Parkinson's disease. O-Glycan Analysis is a useful method for detecting glycan changes in disease.
Fig.2 O-GlcNAcylation and its neuroprotective role in neurons. (Lee, et al, 2021)
Alzheimer's disease is the most common neurodegenerative disorder characterized by progressive mental decline. The study found that the level of O-GlcNAc glycosylation in patients with Alzheimer's disease was 22%-50% lower than that in healthy controls. Amyloid-β and tau proteins play an important role in the pathology of Alzheimer's disease. In Alzheimer's disease patients, tau protein is abnormally hyperphosphorylated and accumulates leading to neurofibrillary tangles (NFTs). O-GlcNAcylation of tau protein can effectively reduce tauopathies. Thus, O-GlcNAcylation is neuroprotective in the brains of Alzheimer's patients.
Parkinson's disease, the second most common neurodegenerative disease after Alzheimer's disease, is mainly caused by the loss of midbrain dopaminergic neurons and functional disruption of basal ganglia circuits. Lewy bodies (LB) composed of abnormal protein aggregation are the main pathological hallmark of Parkinson's disease and α-synuclein is the main component of LB inclusion bodies. Phosphorylation of the protein triggers abnormal aggregation that disrupts cell structure and function, leading to neuronal death. When α-synuclein is glycosylated by O-GlcNAc, abnormal aggregation is significantly reduced, thereby attenuating neuronal toxicity.
Huntington's disease is a rare inherited neurodegenerative disorder caused primarily by mutations of the huntingtin (HTT) gene. Both HTT and huntingtin-interacting protein 1-related protein (HIP1R) are O-GlcNAc modified. Reduction of O-GlcNAcylation levels has the potential to attenuate aggregation and cytotoxicity of pathogenic mutant HTT proteins.
Amyotrophic lateral sclerosis is associated with multiple factors including genetic mutations, abnormal neurofilament function, oxidative stress, and inflammation. Studies have shown that O-GlcNAcylation plays a key role in regulating amyotrophic lateral sclerosis pathology by inhibiting hyperphosphorylation and protein aggregation and reducing reactive oxygen species (ROS) accumulation.
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