title: 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.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arawaka
authors.forename: Manabu
authors.initials: M
authors.lastname: Wada
authors.forename: Saori
authors.initials: S
authors.lastname: Goto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Karube
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Chang-Hong
authors.initials: CH
authors.lastname: Ren
authors.forename: Shingo
authors.initials: S
authors.lastname: Koyama
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanami
authors.forename: Keiji
authors.initials: K
authors.lastname: Kurita
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tajima
authors.forename: Makoto
authors.initials: M
authors.lastname: Daimon
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Takashi
authors.initials: T
authors.lastname: Kido
authors.forename: Sachiko
authors.initials: S
authors.lastname: Saino
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Asao
authors.forename: Chihumi
authors.initials: C
authors.lastname: Kitanaka
authors.forename: Emi
authors.initials: E
authors.lastname: Takashita
authors.forename: Seiji
authors.initials: S
authors.lastname: Hongo
authors.forename: Takao
authors.initials: T
authors.lastname: Nakamura
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Katagiri
authors.forename: Katsuro
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurimura
authors.forename: Itaru
authors.initials: I
authors.lastname: Toyoshima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Niizato
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Hiroto
authors.initials: H
authors.lastname: Matsumine
authors.forename: Takeo
authors.initials: T
authors.lastname: Kato
mesh_terms: D000368:Aged; D001921:Brain / Q000201:enzymology*; D002460:Cell Line; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D016631:Lewy Bodies / Q000201:enzymology*; D008297:Male; D010300:Parkinson Disease / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012008:Recurrence; D014018:Tissue Distribution; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human