Arawaka Shigeki, Wada Manabu, Goto Saori, Karube Hiroki, Sakamoto Masahiro, Ren Chang-Hong, Koyama Shingo, Nagasawa Hikaru, Kimura Hideki, Kawanami Toru, Kurita Keiji, Tajima Katsushi, Daimon Makoto, Baba Masanori, Kido Takashi, Saino Sachiko, Goto Kaoru, Asao Hironobu, Kitanaka Chihumi, Takashita Emi, Hongo Seiji, Nakamura Takao, Kayama Takamasa, Suzuki Yoshihiro, Kobayashi Kazuo, Katagiri Tadashi, Kurokawa Katsuro, Kurimura Masayuki, Toyoshima Itaru, Niizato Kazuhiro, Tsuchiya Kuniaki, Iwatsubo Takeshi, Muramatsu Masaaki, Matsumine Hiroto, Kato Takeo
Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
J Neurosci. 2006 Sep 6;26(36):9227-38. doi: 10.1523/JNEUROSCI.0341-06.2006.
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.
散发性帕金森病（sPD）是一种常见的神经退行性疾病，其特征是黑质中多巴胺能神经元的选择性退化。尽管该疾病的发病机制尚未确定，但α-突触核蛋白的磷酸化及其寡聚体形成似乎起着关键作用。然而，参与sPD发病机制中磷酸化过程的蛋白激酶尚未被鉴定出来。在此，我们发现G蛋白偶联受体激酶5（GRK5）在路易小体中积累，并在sPD患者大脑的病理结构中与α-突触核蛋白共定位。在共转染细胞中，GRK5在质膜上使α-突触核蛋白的Ser-129位点磷酸化，并诱导磷酸化的α-突触核蛋白向核周区域转运。GRK5催化的磷酸化还促进了α-突触核蛋白可溶性寡聚体和聚集体的形成。遗传关联研究揭示了GRK5基因单倍型与sPD易感性的关联。该单倍型在GRK5基因内含子中包含两个功能性单核苷酸多态性，即m22.1和m24，它们分别与YY1（阴阳-1）和CREB-1（环磷酸腺苷反应元件结合蛋白1）结合，并增加了报告基因的转录活性。结果表明，GRK5介导的α-突触核蛋白磷酸化在sPD的发病机制中起关键作用。
