title: A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo.
abstract: Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K(i) = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Macauley
authors.forename: Julia E
authors.initials: JE
authors.lastname: Heinonen
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Shan
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Dennis
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.forename: Garrett E
authors.initials: GE
authors.lastname: Whitworth
authors.forename: Keith A
authors.initials: KA
authors.lastname: Stubbs
authors.forename: Ernest J
authors.initials: EJ
authors.lastname: McEachern
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D024801:Tauopathies / Q000188:drug therapy*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases