Open AccessThe influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer's disease risk
Author(s) -
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,
Lili Cui
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.20283
Subject(s) - china , medicine , disease , family medicine , gerontology , history , archaeology
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.