Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors.
Abnormal phosphorylation of tau has been considered as a key pathogenic mechanism inducing tau aggregation in multiple neurodegenerative disorders, collectively called tauopathies. Recent evidence showed that tau phosphorylation sites are protected with O-linked β-N-acetylglucosamine (O-GlcNAc) in normal brain. In pathological condition, tau is de-glycosylated and becomes a substrate for kinases. Despite the importance of O-GlcNAcylation in tau pathology, O-GlcNAc transferase (OGT), and an enzyme catalyzing O-GlcNAc to tau, has not been carefully investigated in the context of tau aggregation. Here, we investigated intracellular tau aggregation regulated by BZX2, an inhibitor of OGT. Upon the inhibition of OGT, tau phosphorylation increased 2.0-fold at Ser199 and 1.5-fold at Ser396, resulting in increased tau aggregation. Moreover, the BZX2 induced tau aggregation was efficiently reduced by the treatment of Thiamet G, an inhibitor of O-GlcNAcase (OGA). Our results demonstrated the protective role of OGT in tau aggregation and also suggest the counter-regulatory mechanism of OGA and OGT in tau pathology.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea. sungsulim85@gmail.com.
Sungsu
S
Lim
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea. mamunbge@gmail.com.|Biological Chemistry, University of Science and Technology (UST), Daejeon 305-333, South Korea. mamunbge@gmail.com.
Md Mamunul
MM
Haque
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea. gsnam@kist.re.kr.
Ghilsoo
G
Nam
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea. ryoo8099@gmail.com.
Nayeon
N
Ryoo
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea. hrhim@kist.re.kr.|Department of Neuroscience, University of Science and Technology (UST), Daejeon 305-333, South Korea. hrhim@kist.re.kr.
Hyewhon
H
Rhim
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea. yunkyungkim@kist.re.kr.|Biological Chemistry, University of Science and Technology (UST), Daejeon 305-333, South Korea. yunkyungkim@kist.re.kr.
Yun Kyung
YK
Kim
D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology; D024801:Tauopathies / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D011714:Pyrans; D013844:Thiazoles; D016875:tau Proteins; C572247:thiamet G; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase
O-GlcNAc transferase; O-GlcNAcase; O-GlcNAcylation; tau aggregation; tau phosphorylation; tau protein