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 S1P2 receptor-mediated signalling. Both wild-type and α-Syn(A53T), a mutant found in familiar PD, caused uncoupling of S1P1 receptor, although α-Syn(A53T) showed stronger potency in uncoupling. Moreover, S1P1 receptor-mediated β-arrestin signal was unaltered by α-Syn(A53T). These results suggest that exogenous α-Syn modulates S1P1 receptor-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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder
Recent studies suggest that α-Syn is detected in cerebrospinal fluid and plasma[16,17], and cell-to-cell transmission of α-Syn plays a role in the progression of PD, i.e., α-Syn pathology is initiated in the peripheral nervous system and olfactory bulb, ascends toward the brainstem and into the midbrain such as substantia nigra, and eventually spreads to the forebrain as suggested by “Braak’s hypothesis”[18]
To identify signalling pathway, which is important in platelet-derived growth factor (PDGF)-induced chemotaxis and that is sensitive to extracellular α-Syn, we first examined the involvement of sphingosine 1-phosphate (S1P) signalling in this phenomenon
Summary
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. We show that impairment of plateletderived 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. S1P binds to members of GTP-binding protein (G-protein)-coupled S1P receptor family (S1P1–5) and triggers diverse cellular processes, including cell angiogenesis, cardiac development, immunity, cell motility, neurotransmitter release and endosome maturation[23,24,25,26] From this background we have studied the extracellular effects of α-Syn on S1P signalling-mediated cell motility using both functional and fluorescence resonance energy transfer (FRET)-based structural analyses. A possible interpretation of α-Syn-induced changes in cellular signalling in conjunction with pathophysiological relevance is discussed
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