The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease.
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.
Arawaka
Shigeki
S
Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
Wada
Manabu
M
Goto
Saori
S
Karube
Hiroki
H
Sakamoto
Masahiro
M
Ren
Chang-Hong
CH
Koyama
Shingo
S
Nagasawa
Hikaru
H
Kimura
Hideki
H
Kawanami
Toru
T
Kurita
Keiji
K
Tajima
Katsushi
K
Daimon
Makoto
M
Baba
Masanori
M
Kido
Takashi
T
Saino
Sachiko
S
Goto
Kaoru
K
Asao
Hironobu
H
Kitanaka
Chihumi
C
Takashita
Emi
E
Hongo
Seiji
S
Nakamura
Takao
T
Kayama
Takamasa
T
Suzuki
Yoshihiro
Y
Kobayashi
Kazuo
K
Katagiri
Tadashi
T
Kurokawa
Katsuro
K
Kurimura
Masayuki
M
Toyoshima
Itaru
I
Niizato
Kazuhiro
K
Tsuchiya
Kuniaki
K
Iwatsubo
Takeshi
T
Muramatsu
Masaaki
M
Matsumine
Hiroto
H
Kato
Takeo
T
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*
D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human