The Role of G-Protein-Coupled Receptor Kinase 5 in Pathogenesis of Sporadic Parkinson's Disease

• Published in: The Journal of neuroscience Vol. 26; no. 36; pp. 9227 - 9238
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 06.09.2006; Society for Neuroscience
• Subjects: Aged; alpha-Synuclein - metabolism; Brain - enzymology; Cell Line; Female; G-Protein-Coupled Receptor Kinase 5; Humans; Kidney - enzymology; Lewy Bodies - enzymology; Male; Parkinson Disease - enzymology; Protein-Serine-Threonine Kinases - metabolism; Recurrence; Tissue Distribution
• ISSN: 0270-6474; 1529-2401
• 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.