α-Synuclein mediates alterations in membrane conductance: a potential role for α-synuclein oligomers in cell vulnerability

Authors

  • Li Rebekah Feng,

    1. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC 20057, USA
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  • Howard J. Federoff,

    1. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC 20057, USA
    2. Department of Neurology, Georgetown University Medical Center, Washington, DC, USA
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  • Stefano Vicini,

    1. Department of Physiology & Biophysics, Georgetown University Medical Center, Washington, DC, USA
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  • Kathleen A. Maguire-Zeiss

    1. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC 20057, USA
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Dr K. A. Maguire-Zeiss, as above.
E-mail: km445@georgetown.edu

Abstract

α-Synuclein has been linked to the pathogenesis of Parkinson’s disease and other synucleinopathies through its propensity to form toxic oligomers. The exact mechanism for oligomeric synuclein-directed cell vulnerability has not been fully elucidated, but one hypothesis portends the formation of synuclein-containing pores within cell membranes leading to leak channel-mediated calcium influx and subsequent cell death. Here we demonstrate synuclein-induced formation of sodium dodecyl sulfate-stable oligomers, intracellular synuclein-positive aggregates, alterations in membrane conductance reminiscent of leak channels and subsequent cytotoxicity in a dopaminergic-like cell line. Furthermore we demonstrate that the synuclein-induced membrane conductance changes are blocked by direct extracellular application of an anti-synuclein antibody. The work presented here confirms that synuclein overexpression leads to membrane conductance changes and demonstrates for the first time through antibody-blocking studies that synuclein plays a direct role in the formation of leak channels.

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