single-channel electrophysiology reveals a distinct and uniform pore complex formed by α-synuclein oligomers in lipid membranes单通道电生理学揭示了一个独特的和统一的孔隙形成的复杂α-synuclein脂质膜的低聚物.pdfVIP

Single-Channel Electrophysiology Reveals a Distinct and Uniform Pore Complex Formed by a-Synuclein Oligomers in Lipid Membranes 1,2 1 1,3 2 2 ¨ 1 Felix Schmidt , Johannes Levin , Frits Kamp , Hans Kretzschmar , Armin Giese *, Kai Botzel ¨ ¨ ¨ ¨ ¨ ¨ 1 Neurologische Klinik, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany, 2 Zentrum fur Neuropathologie und ¨ ¨ ¨ ¨ Prionforschung, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany, 3 Deutsches Zentrum fur Neurodegenerative Erkrankungen und Adolf-Butenandt-Institut, ¨ ¨ ¨ Ludwig-Maximilians-Universitat Munchen, Munchen, Germany Abstract Synucleinopathies such as Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies are characterized by deposition of aggregated a-synuclein. Recent findings indicate that pathological oligomers rather than fibrillar aggregates may represent the main toxic protein species. It has been shown that a-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 a-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 o