The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease
The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease
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DOI：
10.1523/jneurosci.0341-06.2006
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发表时间：
2006-09-06
影响因子：
5.3
通讯作者：
Kato, Takeo
中科院分区：
文献类型：
--
作者：
Arawaka, Shigeki;Wada, Manabu;Kato, Takeo
散发性帕金森病（sPD）是一种常见的神经退行性疾病，其特征是黑质多巴胺能神经元的选择性变性。虽然疾病的发病机制尚不清楚，但α -突触核蛋白的磷酸化及其寡聚物的形成似乎起着关键作用。然而，sPD发病机制中参与磷酸化的蛋白激酶尚未被确定。本研究发现，g蛋白偶联受体激酶5 （GRK5）在sPD患者的大脑病理结构中与路易小体积累并与α -突触核蛋白共定位。在共转染的细胞中，GRK5磷酸化了质膜上α -突触核蛋白的Ser-129，并诱导磷酸化的α -突触核蛋白易位到核周区。grk5催化的磷酸化也促进了可溶性低聚物和α -突触核蛋白聚集物的形成。遗传关联研究显示GRK5基因与sPD易感性存在单倍型关联。该单倍型在GRK5基因内含子中含有两个功能性单核苷酸多态性m22.1和m24，分别与YY1（阴阳-1）和CREB-1 （cAMP反应元件结合蛋白1）结合，增加了报告基因的转录活性。结果表明，GRK5对α -突触核蛋白的磷酸化在sPD的发病机制中起着至关重要的作用。
Sporadic Parkinson's disease (sPD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Although the pathogenesis of the disease remains undetermined, phosphorylation of alpha-synuclein and its oligomer formation seem to play a key role. However, the protein kinase(s) involved in the phosphorylation in the pathogenesis of sPD has not been identified. Here, we found that G-protein-coupled receptor kinase 5 (GRK5) accumulated in Lewy bodies and colocalized with alpha-synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein. Genetic association study revealed haplotypic association of the GRK5 gene with susceptibility to sPD. The haplotype contained two functional single-nucleotide polymorphisms, m22.1 and m24, in introns of the GRK5 gene, which bound to YY1 (Yin Yang-1) and CREB-1 (cAMP response element-binding protein 1), respectively, and increased transcriptional activity of the reporter gene. The results suggest that phosphorylation of alpha-synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.