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Author Notes:

Correspondence: Xiaochuan Wang, Email: wxch@mails.tjmu.edu.cn.

XW designed the research.

QZ, YX, YW, YS, KZ, YM, FH, MW, DK, and QW performed the research.

BZ, RL, J-ZW, KY, and XW analyzed the data.

KY and XW wrote the paper.

We thank all the members of Jiang lab for the critical comments and helpful discussions on this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All animal experiments were approved by the Animal Care and Use Committee of Huazhong University of Science and Technology and performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Research Funding:

This work was supported in part by grants from the National Natural Science Foundation of China (81571255, 31771114, and 31528010), grant from the Innovative Research Groups of the National Natural Science Foundation of China (81721005), grant from the Ministry of Science and Technology of China (2016YFC1305800), and grant from the Academic Frontier Youth Team Project to XW from Huazhong University of Science and Technology.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • casein kinase 2 (CK2)
  • Alzheimer disease (AD)
  • SET
  • tau phosphorylation
  • cognitive impairment
  • PROTEIN-KINASE CK2
  • ALZHEIMERS-DISEASE
  • ABNORMAL HYPERPHOSPHORYLATION
  • NEURODEGENERATIVE DISEASES
  • ASPARAGINE ENDOPEPTIDASE
  • INHIBITION
  • PHOSPHATASE-2A
  • ACTIVATION
  • LOCALIZATION
  • ACCUMULATION

CK2 Phosphorylating I-2(PP2A)/SET Mediates Tau Pathology and Cognitive Impairment

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Journal Title:

Frontiers in Molecular Neurosciencee

Volume:

Volume 11

Publisher:

, Pages 146-146

Type of Work:

Article | Final Publisher PDF

Abstract:

Casein kinase 2 (CK2) is highly activated in Alzheimer disease (AD) and is associated with neurofibrillary tangles formation. Phosphorylated SET, a potent PP2A inhibitor, mediates tau hyperphosphorylation in AD. However, whether CK2 phosphorylates SET and regulates tau pathological phosphorylation in AD remains unclear. Here, we show that CK2 phosphorylating SET at Ser9 induced tau hyperphosphorylation in AD. We found that either Aβ treatment or tau overexpression stimulated CK2 activation leading to SET Ser9 hyperphosphorylation in neurons and animal models, while inhibition of CK2 by TBB abolished this event. Overexpression of CK2 in mouse hippocampus via virus injection induced cognitive deficit associated with SET Ser9 hyperphosphorylation. Injection of SET Ser9 phosphorylation mimetic mutant induced tau pathology and behavior impairments. Conversely co-injection of non-phosphorylated SET S9A with CK2 abolished the CK2 overexpression-induced AD pathology and cognitive deficit. Together, our data demonstrate that CK2 phosphorylates SET at Ser9 leading to SET cytoplasmic translocation and inhibition of PP2A resulting in tau pathology and cognitive impairments.

Copyright information:

© 2018 Zhang, Xia, Wang, Shentu, Zeng, Mahaman, Huang, Wu, Ke, Wang, Zhang, Liu, Wang, Ye and Wang.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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