G protein-coupled receptor kinase 5, overexpressed in the α-synuclein up-regulation model of Parkinson's disease, regulates bcl-2 expression

G protein-coupled receptor kinase 5 (GRK5) has been reported to accumulate in Lewy bodies (LBs), a histological hallmark of Parkinson's disease. Recent findings propose that GRK5 might function in Parkinson's disease via phosphorylation of alpha-synuclein, a major component of LBs. In this study, the changes of the expression levels of GRK5 and its possible effects in Parkinson's disease were evaluated in cell lines and transgenic mice model of alpha-synuclein overexpression. Both the expression levels of cytoplasmic and nuclear distributed GRKS were induced an increase via alpha-synuclein overexpression in vivo and in vitro. The observations that the levels of alpha-synuclein phosphorylated at Ser-129 (pS129-alpha-synuclein) remain unchanged despite the downregulation of GRK5 by short hairpin ribonucleic acid (shRNA) transfection suggest that GRK5 is not the sole kinase involved in phosphorylating alpha-synuclein in Parkinson's disease. In addition, the findings that nuclear accumulation of GRKS inhibits bcl-2 transcription and expression, at least in part by enhancing histone deacetylase (HDAC) activity, show an unexpected role for nuclear GRK5 in the regulation of an apoptosis-related gene. The present study suggests that GRK5 may be extensively involved in the mechanism of Parkinson's disease. (C) 2009 Elsevier B.V. All rights reserved.