title: Human α4β2 nicotinic acetylcholine receptor as a novel target of oligomeric α-synuclein.
abstract: Cigarette smoking is associated with a decreased incidence of Parkinson disease (PD) through unknown mechanisms. Interestingly, a decrease in the numbers of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in PD patients suggests an α4β2-nAChR-mediated cholinergic deficit in PD. Although oligomeric forms of α-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 α-synuclein selectively inhibits human α4β2-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 α-synuclein-induced inhibition of α4β2-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 α-synuclein on α4β2-nAChRs, but not on α4β4- or α7-nAChRs, suggesting nAChR subunit selectivity of oligomeric α-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 α-synuclein aggregates (but not monomeric, small oligomeric or fibrillar α-synuclein aggregates) exhibit the inhibitory effect on human α4β2-nAChRs. Collectively, we have provided direct evidence that α4β2-nAChR is a sensitive target to mediate oligomeric α-synuclein-induced modulation of cholinergic signaling, and our data imply that therapeutic strategies targeted toward α4β2-nAChRs may have potential for developing new treatments for PD.
authors: Division of Neurology, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
authors: Qiang
authors: Q
authors: Liu
authors: Sharareh
authors: S
authors: Emadi
authors: Jian-Xin
authors: JX
authors: Shen
authors: Michael R
authors: MR
authors: Sierks
authors: Jie
authors: J
authors: Wu
mesh_terms: D002850:Chromatography, Gel; D004705:Endocytosis; D006801:Humans; D015640:Ion Channel Gating; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011978:Receptors, Nicotinic / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011978:Receptors, Nicotinic; D051844:alpha-Synuclein; C497604:SNCA protein, human; C403531:nicotinic receptor alpha4beta2