Extracellular ?-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving ?-arrestin signal intact.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of ?-synuclein (?-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 ?-Syn plays a role in the progression of PD. Although extracellular ?-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 ?-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling. Treatment of human neuroblastoma cells with recombinant ?-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, ?-Syn caused little or no effect on S1P2 receptor-mediated signalling. Both wild-type and ?-Syn(A53T), a mutant found in familiar PD, caused uncoupling of S1P1 receptor, although ?-Syn(A53T) showed stronger potency in uncoupling. Moreover, S1P1 receptor-mediated ?-arrestin signal was unaltered by ?-Syn(A53T). These results suggest that exogenous ?-Syn modulates S1P1 receptor-mediated signalling from both Gi and ?-arrestin signals into ?-arrestin-biased signal. These findings uncovered a novel function of exogenous ?-Syn in the cells.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC5353548 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature