Alpha-synuclein mediates alterations in membrane conductance: a potential role for alpha-synuclein oligomers in cell vulnerability.
alpha-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.
Feng
Li Rebekah
LR
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Federoff
Howard J
HJ
Vicini
Stefano
S
Maguire-Zeiss
Kathleen A
KA
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004553:Electric Conductivity; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism; D055503:Protein Multimerization; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D024683:Potassium Channels, Tandem Pore Domain; D051844:alpha-Synuclein; D004298:Dopamine