O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease.
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains of individuals with Alzheimer's disease (AD) and other tauopathies. Tau pathology is critical to pathogenesis and correlates to the severity of dementia. However, the mechanisms leading to abnormal hyperphosphorylation are unknown. Here, we demonstrate that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide beta-N-acetylglucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond. O-GlcNAcylation regulated phosphorylation of tau in a site-specific manner both in vitro and in vivo. At most of the phosphorylation sites, O-GlcNAcylation negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake/metabolism that mimicked those observed in AD brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in AD brain extracts was decreased as compared to that in controls. These results reveal a mechanism of regulation of tau phosphorylation and suggest that abnormal hyperphosphorylation of tau could result from decreased tau O-GlcNAcylation, which probably is induced by deficient brain glucose uptake/metabolism in AD and other tauopathies.
Liu
Fei
F
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Iqbal
Khalid
K
Grundke-Iqbal
Inge
I
Hart
Gerald W
GW
Gong
Cheng-Xin
CX
D000117:Acetylglucosamine / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D013217:Starvation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016875:tau Proteins; D000117:Acetylglucosamine