Human α4β2 Nicotinic Acetylcholine Receptor as a Novel Target of Oligomeric α-Synuclein

Qiang Liu, Sharareh Emadi, Jian Xin Shen, Michael Sierks, Jie Wu

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere55886
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 20 2013

Fingerprint

Synucleins
cholinergic receptors
Parkinson disease
Nicotinic Receptors
cholinergic agents
Parkinson Disease
protein aggregates
Cholinergic Agents
thiophosphate
atomic force microscopy
smoking (habit)
pathogenesis
Size exclusion chromatography
Atomic Force Microscopy
Poisons
incidence
therapeutics
Tobacco Products
Gel Chromatography
Atomic force microscopy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Human α4β2 Nicotinic Acetylcholine Receptor as a Novel Target of Oligomeric α-Synuclein. / Liu, Qiang; Emadi, Sharareh; Shen, Jian Xin; Sierks, Michael; Wu, Jie.

In: PLoS One, Vol. 8, No. 2, e55886, 20.02.2013.

Research output: Contribution to journalArticle

Liu, Qiang ; Emadi, Sharareh ; Shen, Jian Xin ; Sierks, Michael ; Wu, Jie. / Human α4β2 Nicotinic Acetylcholine Receptor as a Novel Target of Oligomeric α-Synuclein. In: PLoS One. 2013 ; Vol. 8, No. 2.
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