O-GlcNAc modification in diabetes and Alzheimer's disease.
Similar to phosphorylation, O-GlcNAcylation (or simply GlcNAcylation) is an abundant, dynamic, and inducible post-translational modification. In some cases, GlcNAcylation and phosphorylation occur at the same or adjacent sites, modulating each other. GlcNAcylated proteins are crucial in regulating virtually all cellular processes, including signaling, cell cycle, and transcription, among others. GlcNAcylation affects protein-protein interactions, activity, stability, and expression. Several GlcNAcylated proteins are involved in diabetes and Alzheimer's disease. Hyperglycemia increases GlcNAcylation of proteins within the insulin signaling pathway and contributes to insulin resistance. In addition, hyperinsulinemia and hyperlipidemia are also associated with increased GlcNAcylation, which affect and regulate several insulin signaling proteins, as well as proteins involved on the pathology of diabetes. With respect to Alzheimer's disease, several proteins involved in the etiology of the disease, including tau, neurofilaments, beta-amyloid precursor protein, and synaptosomal proteins are GlcNAcylated in normal brain. The impairment of brain glucose uptake/metabolism is a known metabolic defect in Alzheimer's neurons. Data support the hypothesis that hypoglycemia within the brain may reduce the normal GlcNAcylation of tau, exposing kinase acceptor sites, thus leading to hyperphosphorylation, which induces tangle formation and neuronal death. Alzheimer's disease and type II diabetes represent two metabolic disorders where dysfunctional protein GlcNAcylation/phosphorylation may be important for disease pathology.
Dias
Wagner B
WB
Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185.
Hart
Gerald W
GW
D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D000544:Alzheimer Disease / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011499:Protein Processing, Post-Translational
D000117:Acetylglucosamine