Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 16, Issue 9, Pages 20212-20224Publisher
MDPI AG
DOI: 10.3390/ijms160920212
Keywords
tau protein; O-GlcNAcylation; O-GlcNAc transferase; O-GlcNAcase; tau phosphorylation; tau aggregation
Funding
- Korea Institute of Science and Technology [2E25240, 2E25473]
- National Research Foundation (NRF)
- center for Women in Science, Engineering and Technology (WISET)
- Ministry of Science, ICT and Future Planning (MSIP) [KW-2014-PPD-0076]
- Rural Development Administration (RDA) [PJ009103]
- Korea Atomic Energy Research Institute (KAERI) - Korea government (Ministry of Science, Information and Communication Technology (ICT) and Future Planning) [698214-14]
- National Medical Research Council [NMRC/CBRG/0015/2012]
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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 -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.
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