title: Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.
abstract: Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Shan
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Macauley
authors.forename: Thomas
authors.initials: T
authors.lastname: Clark
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Skorobogatko
authors.forename: Keith
authors.initials: K
authors.lastname: Vosseller
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002236:Carbohydrate Conformation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011714:Pyrans / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D011714:Pyrans; C531463:Tab1 protein, mouse; D013844:Thiazoles; D016875:tau Proteins; C572247:thiamet G; D017351:N-Acetylglucosaminyltransferases; D000117:Acetylglucosamine