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.

Exposure of a-synuclein (aS), a major component of Lewy bodies in ParkinsonÕs disease, to polyunsaturated fatty acids (PUFAs) triggers the formation of soluble aS oligomers. Here, we demonstrate that PUFA binds recombinant aS protein through its N-terminal region (residues 2-60). In HEK293 cells, aS mutants lacking the N-terminal region failed to form oligomers in the presence of PUFA. The PUFA-induced aS oligomerization was accelerated by C-terminal truncation or Ser129 phosphorylation of aS; however, this effect was abolished by deletion of the N-terminus. The results indicate that the N-terminus of aS is essential for the PUFA-induced aS oligomerization.