The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease.

Abstract

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.

• Authors: Shigeki Arawaka, Manabu Wada, Saori Goto, Hiroki Karube, Masahiro Sakamoto, Chang-Hong Ren, Shingo Koyama, Hikaru Nagasawa, Hideki Kimura, Toru Kawanami, Keiji Kurita, Katsushi Tajima, Makoto Daimon, Masanori Baba, Takashi Kido, Sachiko Saino, Kaoru Goto, Hironobu Asao, Chihumi Kitanaka, Emi Takashita, Seiji Hongo, Takao Nakamura, Takamasa Kayama, Yoshihiro Suzuki, Kazuo Kobayashi, Tadashi Katagiri, Katsuro Kurokawa, Masayuki Kurimura, Itaru Toyoshima, Kazuhiro Niizato, Kuniaki Tsuchiya, Takeshi Iwatsubo, Masaaki Muramatsu, Hiroto Matsumine, Takeo Kato
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 26 Issue 36 Pg. 9227-38 (Sep 06 2006) ISSN: 1529-2401 [Electronic] United States
• PMID: 16957079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Synuclein
• Protein Serine-Threonine Kinases
• G-Protein-Coupled Receptor Kinase 5
• GRK5 protein, human

Topics

• Aged
• 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
• alpha-Synuclein (metabolism)