A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

TY - JOUR

T1 - A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

AU - Yuzwa, Scott A.

AU - Macauley, Matthew S.

AU - Heinonen, Julia E.

AU - Shan, Xiaoyang

AU - Dennis, Rebecca J.

AU - He, Yuan

AU - Whitworth, Garrett E.

AU - Stubbs, Keith A.

AU - McEachern, Ernest J.

AU - Davies, Gideon J.

AU - Vocadlo, David J.

PY - 2008/8

Y1 - 2008/8

N2 - 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.

AB - 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.

KW - BETA-N-ACETYLGLUCOSAMINIDASE

KW - PAIRED HELICAL FILAMENTS

KW - GLYCOGEN-SYNTHASE KINASE-3-BETA

KW - SUBSTRATE-ASSISTED CATALYSIS

KW - TETRATRICOPEPTIDE REPEATS

KW - NEUROFIBRILLARY TANGLES

KW - ALZHEIMERS-DISEASE

KW - CYTOSOLIC PROTEINS

KW - D-GLUCOSAMINIDASE

KW - NAG-THIAZOLINE

UR - http://www.scopus.com/inward/record.url?scp=47649114560&partnerID=8YFLogxK

U2 - 10.1038/nchembio.96

DO - 10.1038/nchembio.96

M3 - Article

SN - 1552-4450

VL - 4

SP - 483

EP - 490

JO - NATURE CHEMICAL BIOLOGY

JF - NATURE CHEMICAL BIOLOGY

IS - 8

ER -