title: Extracellular α-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving β-arrestin signal intact.
abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling. Treatment of human neuroblastoma cells with recombinant α-Syn caused S1P type 1 (S1P1) receptor-selective uncoupling from inhibitory G-protein (Gi) as determined by both functional and fluorescence resonance energy transfer (FRET)-based structural analyses. By contrast, α-Syn caused little or no effect on S1P2receptor-mediated signalling. Both wild-type and α-Syn(A53T), a mutant found in familiar PD, caused uncoupling of S1P1receptor, although α-Syn(A53T) showed stronger potency in uncoupling. Moreover, S1P1receptor-mediated β-arrestin signal was unaltered by α-Syn(A53T). These results suggest that exogenous α-Syn modulates S1P1receptor-mediated signalling from both Gi and β-arrestin signals into β-arrestin-biased signal. These findings uncovered a novel function of exogenous α-Syn in the cells.
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: Taro
authors.identifier: `
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: Shaymaa Mohamed Mohadmed
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: 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: 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; D002465:Cell Movement / Q000187:drug effects; D031541:Fluorescence Resonance Energy Transfer; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000071557:beta-Arrestins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D051844:alpha-Synuclein; D000071557:beta-Arrestins; C075278:platelet-derived growth factor A; C060506:sphingosine 1-phosphate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D013110:Sphingosine