title: Impairment of PDGF-induced chemotaxis by extracellular α-synuclein through selective inhibition of Rac1 activation.
abstract: Parkinson's disease (PD) is characterized by α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies. Although it is known that extracellular α-Syn is detected in the plasma and cerebrospinal fluid, its physiological significance remains unclear. Here, we show that extracellular α-Syn suppresses platelet-derived growth factor (PDGF)-induced chemotaxis in human neuroblastoma SH-SY5Y cells. The inhibitory effect was stronger in the mutant α-Syn(A53T), found in hereditary PD, and the degree of inhibition was time-dependent, presumably because of the oligomerization of α-Syn. PDGF-induced activation of Akt or Erk was not influenced by α-Syn(A53T). Further studies revealed that α-Syn(A53T) inhibited PDGF-induced Rac1 activation, whereas Cdc42 activation remained unaffected, resulting in unbalanced actin filament remodeling. These results shed light on the understanding of pathological as well as physiological functions of extracellular α-Syn in neuronal cells.
authors.affiliation: Division of Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Okada
authors.affiliation: Division of Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Chihoko
authors.initials: C
authors.lastname: Hirai
authors.affiliation: Division of Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Shaymaa Mohamed Mohamed
authors.initials: SMM
authors.lastname: Badawy
authors.affiliation: Division of Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Kajimoto
authors.affiliation: Division of Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Shun-Ichi
authors.initials: SI
authors.lastname: Nakamura
mesh_terms: D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000502:physiology*; D006801:Humans; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D010982:Platelet-Derived Growth Factor; C107953:RAC1 protein, human; D051844:alpha-Synuclein; D020830:rac1 GTP-Binding Protein