Oncotarget

Research Papers:

The influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer’s disease risk

Yuan Zhang, Jianghao Zhao, Mingkang Yin, Yujie Cai, Shengyuan Liu, Yan Wang, Xingliang Zhang, Hao Cao, Ting Chen, Pengru Huang, Hui Mai, Zhou Liu, Hua Tao, Bin Zhao _ and Lili Cui

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Oncotarget. 2017; 8:72714-72726. https://doi.org/10.18632/oncotarget.20283

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Abstract

Yuan Zhang1,2,*, Jianghao Zhao1,*, Mingkang Yin1,*, Yujie Cai1, Shengyuan Liu3, Yan Wang4, Xingliang Zhang5, Hao Cao6, Ting Chen7, Pengru Huang1, Hui Mai1, Zhou Liu1, Hua Tao1, Bin Zhao1 and Lili Cui1

1Guangdong Key Laboratory of Age-related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

2Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China

3Department of Chronic Disease, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, China

4Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China

5Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

6Departments of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China

7Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

*Authors contributed equally to this work

Correspondence to:

Bin Zhao, email: [email protected]

Lili Cui, email: [email protected]

Keywords: GRK5, polymorphisms, p-tau, β-amyloid, Alzheimer’s disease

Received: April 19, 2017    Accepted: July 23, 2017    Published: August 16, 2017

ABSTRACT

Our work explores the relationship between G protein-coupled receptor kinase-5 (GRK5) single nucleotide polymorphisms and Alzheimer’s disease risk. We confirmed that GRK5 translocates from the cellular membrane to the cytosol in the hippocampus of Alzheimer’s disease mice and that GRK5 deficiency promotes tau hyperphosphorylation, a hallmark of Alzheimer’s disease pathology. Our results indicate that one functional variant, or mutant, of GRK5 (GRK5-Gln41Leu) decreased GRK5 translocation from the membrane to the cytoplasm and reduced tau hyperphosphorylation, whereas, another GRK5 mutant (GRK5-Arg304His) increased GRK5 translocation to the cytoplasm and promoted tau hyperphosphorylation. In addition, case-control studies revealed that GRK5-Gln41Leu is associated with a lower risk of late-onset Alzheimer’s disease. Our findings suggest that the GRK5-Gln41Leu mutant may resist tau hyperphosphorylation by promoting GRK5 membrane stability and, in effect, may contribute to lower Alzheimer’s disease risk.


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