Cigarette smoking is associated with a decreased incidence of Parkinson disease (PD) through unknown mechanisms. Interestingly, a decrease in the numbers of Î±4Î²2 nicotinic acetylcholine receptors (Î±4Î²2-nAChRs) in PD patients suggests an Î±4Î²2-nAChR-mediated cholinergic deficit in PD. Although oligomeric forms of Î±-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 Î±-synuclein selectively inhibits human Î±4Î²2-nAChR-mediated currents in a dose-dependent, non-competitive and use-independent manner. We show that pre-loading cells with guanyl-5â€²-yl thiophosphate fails to prevent this inhibition, suggesting that the Î±-synuclein-induced inhibition of Î±4Î²2-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 Î±-synuclein on Î±4Î²2-nAChRs, but not on Î±4Î²4- or Î±7-nAChRs, suggesting nAChR subunit selectivity of oligomeric Î±-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 Î±-synuclein aggregates (but not monomeric, small oligomeric or fibrillar Î±-synuclein aggregates) exhibit the inhibitory effect on human Î±4Î²2-nAChRs. Collectively, we have provided direct evidence that Î±4Î²2-nAChR is a sensitive target to mediate oligomeric Î±-synuclein-induced modulation of cholinergic signaling, and our data imply that therapeutic strategies targeted toward Î±4Î²2-nAChRs may have potential for developing new treatments for PD. Â© 2013 Liu et al.
Digital Object Identifier (DOI)
Liu, Qiang; Emadi, Sharareh; Shen, Jian Xin; Sierks, Michael R.; and Wu, Jie, "Human Î±4Î²2 Nicotinic Acetylcholine Receptor As A Novel Target Of Oligomeric Î±-Synuclein" (2013). Neurobiology. 146.