RT Journal Article
SR Electronic
T1 The Role of G-Protein-Coupled Receptor Kinase 5 in Pathogenesis of Sporadic Parkinson's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9227
OP 9238
DO 10.1523/JNEUROSCI.0341-06.2006
VO 26
IS 36
A1 Shigeki Arawaka
A1 Manabu Wada
A1 Saori Goto
A1 Hiroki Karube
A1 Masahiro Sakamoto
A1 Chang-Hong Ren
A1 Shingo Koyama
A1 Hikaru Nagasawa
A1 Hideki Kimura
A1 Toru Kawanami
A1 Keiji Kurita
A1 Katsushi Tajima
A1 Makoto Daimon
A1 Masanori Baba
A1 Takashi Kido
A1 Sachiko Saino
A1 Kaoru Goto
A1 Hironobu Asao
A1 Chihumi Kitanaka
A1 Emi Takashita
A1 Seiji Hongo
A1 Takao Nakamura
A1 Takamasa Kayama
A1 Yoshihiro Suzuki
A1 Kazuo Kobayashi
A1 Tadashi Katagiri
A1 Katsuro Kurokawa
A1 Masayuki Kurimura
A1 Itaru Toyoshima
A1 Kazuhiro Niizato
A1 Kuniaki Tsuchiya
A1 Takeshi Iwatsubo
A1 Masaaki Muramatsu
A1 Hiroto Matsumine
A1 Takeo Kato
YR 2006
UL http://www.jneurosci.org/content/26/36/9227.abstract
AB 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 α-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 α-synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of α-synuclein at the plasma membrane and induced translocation of phosphorylated α-synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of α-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 α-synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.