Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5, Panjiayuan, Nanli, Chaoyang District, Beijing 100021, PR China.
Brain Res. 2010 Jan 11;1307:134-41. doi: 10.1016/j.brainres.2009.10.036. Epub 2009 Oct 21.
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 GRK5 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 GRK5 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.
G 蛋白偶联受体激酶 5（GRK5）已被报道在路易体（LB）中积累，这是帕金森病的组织学标志。最近的研究结果表明，GRK5 可能通过磷酸化 LB 的主要成分α-突触核蛋白在帕金森病中发挥作用。在这项研究中，评估了 GRK5 的表达水平变化及其在α-突触核蛋白过表达的细胞系和转基因小鼠模型中可能的作用。体内和体外α-突触核蛋白过表达均诱导细胞质和核分布的 GRK5 表达水平增加。尽管短发夹 RNA（shRNA）转染下调 GRK5，但 Ser-129 磷酸化的α-突触核蛋白（pS129-α-突触核蛋白）水平保持不变的观察结果表明，GRK5 不是参与帕金森病中磷酸化α-突触核蛋白的唯一激酶。此外，GRK5 核积累抑制 bcl-2 转录和表达的发现，至少部分是通过增强组蛋白去乙酰化酶（HDAC）活性，显示核 GRK5 在调节与凋亡相关基因中的作用出乎意料。本研究表明，GRK5 可能广泛参与帕金森病的发病机制。
