TY  - JOUR
AU  - Schmidt, Felix
AU  - Levin, Johannes
AU  - Kamp, Frits
AU  - Kretzschmar, Hans
AU  - Giese, Armin
AU  - Bötzel, Kai
TI  - Single-channel electrophysiology reveals a distinct and uniform pore complex formed by α-synuclein oligomers in lipid membranes.
JO  - PLOS ONE
VL  - 7
IS  - 8
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-02918
SP  - e42545
PY  - 2012
AB  - 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.
KW  - Cations
KW  - Electric Conductivity
KW  - Electrophysiological Phenomena
KW  - Humans
KW  - Lipid Bilayers: metabolism
KW  - Models, Biological
KW  - Porosity
KW  - Protein Structure, Quaternary
KW  - Time Factors
KW  - alpha-Synuclein: chemistry
KW  - alpha-Synuclein: metabolism
KW  - Cations (NLM Chemicals)
KW  - Lipid Bilayers (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22880029
C2  - pmc:PMC3411845
DO  - DOI:10.1371/journal.pone.0042545
UR  - https://pub.dzne.de/record/136596
ER  -