Single-Channel Electrophysiology Reveals a Distinct and Uniform Pore Complex Formed by α-Synuclein Oligomers in Lipid Membranes

Hdl Handle:
http://hdl.handle.net/10675.2/818
Title:
Single-Channel Electrophysiology Reveals a Distinct and Uniform Pore Complex Formed by α-Synuclein Oligomers in Lipid Membranes
Authors:
Schmidt, Felix; Levin, Johannes; Kamp, Frits; Kretzschmar, Hans; Giese, Armin; Botzel, Kai
Abstract:
Synucleinopathies such as Parkinson's disease, multiple system atrophy and dementia with Lewy bodies are characterized by deposition of aggregated α-synuclein. Recent findings indicate that pathological oligomers rather than fibrillar aggregates may represent the main toxic protein species. It has been shown that α-synuclein oligomers can increase the conductance of lipid bilayers and, in cell-culture, lead to calcium dyshomeostasis and cell death. In this study, employing a setup for single-channel electrophysiology, we found that addition of iron-induced α-synuclein oligomers resulted in quantized and stepwise increases in bilayer conductance indicating insertion of distinct transmembrane pores. These pores switched between open and closed states depending on clamped voltage revealing a single-pore conductance comparable to that of bacterial porins. Pore conductance was dependent on transmembrane potential and the available cation. The pores stably inserted into the bilayer and could not be removed by buffer exchange. Pore formation could be inhibited by co-incubation with the aggregation inhibitor baicalein. Our findings indicate that iron-induced α-synuclein oligomers can form a uniform and distinct pore species with characteristic electrophysiological properties. Pore formation could be a critical event in the pathogenesis of synucleinopathies and provide a novel structural target for disease-modifying therapy.
Editors:
Tsien, Joe Z.
Citation:
PLoS One. 2012 Aug 3; 7(8):e42545
Issue Date:
3-Aug-2012
URI:
http://hdl.handle.net/10675.2/818
DOI:
10.1371/journal.pone.0042545
PubMed ID:
22880029
PubMed Central ID:
PMC3411845
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorSchmidt, Felixen_US
dc.contributor.authorLevin, Johannesen_US
dc.contributor.authorKamp, Fritsen_US
dc.contributor.authorKretzschmar, Hansen_US
dc.contributor.authorGiese, Arminen_US
dc.contributor.authorBotzel, Kaien_US
dc.contributor.editorTsien, Joe Z.-
dc.date.accessioned2012-10-26T20:35:10Z-
dc.date.available2012-10-26T20:35:10Z-
dc.date.issued2012-08-3en_US
dc.identifier.citationPLoS One. 2012 Aug 3; 7(8):e42545en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22880029en_US
dc.identifier.doi10.1371/journal.pone.0042545en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/818-
dc.description.abstractSynucleinopathies such as Parkinson's disease, multiple system atrophy and dementia with Lewy bodies are characterized by deposition of aggregated α-synuclein. Recent findings indicate that pathological oligomers rather than fibrillar aggregates may represent the main toxic protein species. It has been shown that α-synuclein oligomers can increase the conductance of lipid bilayers and, in cell-culture, lead to calcium dyshomeostasis and cell death. In this study, employing a setup for single-channel electrophysiology, we found that addition of iron-induced α-synuclein oligomers resulted in quantized and stepwise increases in bilayer conductance indicating insertion of distinct transmembrane pores. These pores switched between open and closed states depending on clamped voltage revealing a single-pore conductance comparable to that of bacterial porins. Pore conductance was dependent on transmembrane potential and the available cation. The pores stably inserted into the bilayer and could not be removed by buffer exchange. Pore formation could be inhibited by co-incubation with the aggregation inhibitor baicalein. Our findings indicate that iron-induced α-synuclein oligomers can form a uniform and distinct pore species with characteristic electrophysiological properties. Pore formation could be a critical event in the pathogenesis of synucleinopathies and provide a novel structural target for disease-modifying therapy.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectElectrophysiologyen_US
dc.subjectBiochemistryen_US
dc.subjectNeurochemistryen_US
dc.subjectComputational Biologyen_US
dc.subjectComputational Neuroscienceen_US
dc.subjectNeuroscienceen_US
dc.subjectCognitive Neuroscienceen_US
dc.subjectMolecular Neuroscienceen_US
dc.subjectNeurobiology of Disease and Regenerationen_US
dc.subjectNeurophysiologyen_US
dc.subjectMedicineen_US
dc.subjectNeurologyen_US
dc.subjectParkinson Diseaseen_US
dc.titleSingle-Channel Electrophysiology Reveals a Distinct and Uniform Pore Complex Formed by α-Synuclein Oligomers in Lipid Membranesen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3411845en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-

Related articles on PubMed

All Items in Scholarly Commons are protected by copyright, with all rights reserved, unless otherwise indicated.