Human ?4?2 nicotinic acetylcholine receptor as a novel target of oligomeric ?-synuclein.

ABSTRACT: Cigarette smoking is associated with a decreased incidence of Parkinson disease (PD) through unknown mechanisms. Interestingly, a decrease in the numbers of ?4?2 nicotinic acetylcholine receptors (?4?2-nAChRs) in PD patients suggests an ?4?2-nAChR-mediated cholinergic deficit in PD. Although oligomeric forms of ?-synuclein have been recognized to be toxic and involved in the pathogenesis of PD, their direct effects on nAChR-mediated cholinergic signaling remains undefined. Here, we report for the first time that oligomeric ?-synuclein selectively inhibits human ?4?2-nAChR-mediated currents in a dose-dependent, non-competitive and use-independent manner. We show that pre-loading cells with guanyl-5'-yl thiophosphate fails to prevent this inhibition, suggesting that the ?-synuclein-induced inhibition of ?4?2-nAChR function is not mediated by nAChR internalization. By using a pharmacological approach and cultures expressing transfected human nAChRs, we have shown a clear effect of oligomeric ?-synuclein on ?4?2-nAChRs, but not on ?4?4- or ?7-nAChRs, suggesting nAChR subunit selectivity of oligomeric ?-synuclein-induced inhibition. In addition, by combining the size exclusion chromatography and atomic force microscopy (AFM) analyses, we find that only large (>4 nm) oligomeric ?-synuclein aggregates (but not monomeric, small oligomeric or fibrillar ?-synuclein aggregates) exhibit the inhibitory effect on human ?4?2-nAChRs. Collectively, we have provided direct evidence that ?4?2-nAChR is a sensitive target to mediate oligomeric ?-synuclein-induced modulation of cholinergic signaling, and our data imply that therapeutic strategies targeted toward ?4?2-nAChRs may have potential for developing new treatments for PD.

SUBMITTER: Liu Q 

PROVIDER: S-EPMC3577813 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature