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

// Yuan Zhang 1, 2, * , Jianghao Zhao 1, * , Mingkang Yin 1, * , Yujie Cai 1 , Shengyuan Liu 3 , Yan Wang 4 , Xingliang Zhang 5 , Hao Cao 6 , Ting Chen 7 , Pengru Huang 1 , Hui Mai 1 , Zhou Liu 1 , Hua Tao 1 , Bin Zhao 1 and Lili Cui 1 1 Guangdong Key Laboratory of Age-related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China 2 Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China 3 Department of Chronic Disease, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, China 4 Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China 5 Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China 6 Departments of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China 7 Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China * Authors contributed equally to this work Correspondence to: Bin Zhao, email: binzhaoe@163.com Lili Cui, email: cuilili@gdmu.edu.cn 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.