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The Journal of Neuroscience, September 6, 2006, 26(36):9227-9238; doi:10.1523/JNEUROSCI.0341-06.2006

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

Shigeki Arawaka,^1 * Manabu Wada,¹ Saori Goto,¹ Hiroki Karube,¹ Masahiro Sakamoto,¹ Chang-Hong Ren,¹ Shingo Koyama,¹ Hikaru Nagasawa,¹ Hideki Kimura,¹ Toru Kawanami,¹ Keiji Kurita,¹ Katsushi Tajima,¹ Makoto Daimon,¹ Masanori Baba,⁸ Takashi Kido,⁸ Sachiko Saino,² Kaoru Goto,² Hironobu Asao,³ Chihumi Kitanaka,⁴ Emi Takashita,⁵ Seiji Hongo,⁵ Takao Nakamura,⁶ Takamasa Kayama,⁷ Yoshihiro Suzuki,⁹ Kazuo Kobayashi,¹⁰ Tadashi Katagiri,¹¹ Katsuro Kurokawa,¹² Masayuki Kurimura,¹³ Itaru Toyoshima,¹⁴ Kazuhiro Niizato,¹⁵ Kuniaki Tsuchiya,¹⁶ Takeshi Iwatsubo,¹⁷ Masaaki Muramatsu,⁸ Hiroto Matsumine,⁸ and Takeo Kato^1 *

Departments of ¹Neurology, Hematology, Metabolism, Endocrinology and Diabetology, ²Anatomy and Cell Biology, ³Immunology, ⁴Molecular Cancer Science, ⁵Infectious Diseases, ⁶Biomedical Information Engineering, and ⁷Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan, ⁸Hubit Genomics, Tokyo 102-0092, Japan, ⁹Department of Neurology, Yamagata Prefectural Nihonkai Hospital, Yamagata 998-0828, Japan, ¹⁰Department of Neurology, Yamagata City Saiseikan Hospital, Yamagata 990-8533, Japan, ¹¹Department of Neurology, Yamagata Prefectural Kahoku Hospital, Yamagata 999-3511, Japan, ¹²Department of Neurology, Yamagata Prefectural Shinjo Hospital, Yamagata 996-0025, Japan, ¹³Department of Neurology, Yonezawa City Hospital, Yamagata 992-8502, Japan, ¹⁴First Department of Internal Medicine, Akita University School of Medicine, Akita 010-8543, Japan, Departments of ¹⁵Psychiatry and ¹⁶Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital, Tokyo 156-0057, Japan, and ¹⁷Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo 113-0033, Japan

Correspondence should be addressed to Takeo Kato, Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Email: tkato{at}med.id.yamagata-u.ac.jp

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 -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 -synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of -synuclein at the plasma membrane and induced translocation of phosphorylated -synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of -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 -synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.

Key words: -synuclein; GRK5; haplotype; Lewy body; phosphorylation; SNP

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Received Oct. 6, 2005; revised July 24, 2006; accepted July 27, 2006.

Correspondence should be addressed to Takeo Kato, Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Email: tkato{at}med.id.yamagata-u.ac.jp

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				O. S. Gorbatyuk, S. Li, L. F. Sullivan, W. Chen, G. Kondrikova, F. P. Manfredsson, R. J. Mandel, and N. Muzyczka The phosphorylation state of Ser-129 in human {alpha}-synuclein determines neurodegeneration in a rat model of Parkinson disease PNAS, January 15, 2008; 105(2): 763 - 768. [Abstract] [Full Text] [PDF]

				H. Kaneko, A. Kakita, K. Kasuga, H. Nozaki, A. Ishikawa, A. Miyashita, R. Kuwano, G. Ito, T. Iwatsubo, H. Takahashi, et al. Enhanced Accumulation of Phosphorylated {alpha}-Synuclein and Elevated -Amyloid 42/40 Ratio Caused by Expression of the Presenilin-1 {Delta}T440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's Disease J. Neurosci., November 28, 2007; 27(48): 13092 - 13097. [Abstract] [Full Text] [PDF]

				B. Thomas and M. F. Beal Parkinson's disease Hum. Mol. Genet., October 15, 2007; 16(R2): R183 - R194. [Abstract] [Full Text] [PDF]

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