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  Cardiolipin promotes pore-forming activity of alpha-synuclein oligomers in mitochondrial membranes.

Ghio, S., Camilleri, A., Caruana, M., Ruf, V. C., Schmidt, F., Leonov, A., et al. (2019). Cardiolipin promotes pore-forming activity of alpha-synuclein oligomers in mitochondrial membranes. ACS Chemical Neuroscience, 10(8), 3815-3829. doi:10.1021/acschemneuro.9b00320.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-5F90-F Version Permalink: http://hdl.handle.net/21.11116/0000-0004-9A34-4
Genre: Journal Article

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Ghio, S., Author
Camilleri, A., Author
Caruana, M., Author
Ruf, V. C., Author
Schmidt, F., Author
Leonov, A.1, Author              
Ryazanov, S.1, Author              
Griesinger, C.1, Author              
Cauchi, R. J., Author
Kamp, F., Author
Giese, A., Author
Vassallo, N., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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 Abstract: Aggregation of the amyloid-forming α-synuclein (αS) protein is closely associated with the etiology of Parkinson's disease (PD), the most common motor neurodegenerative disorder. Many studies have shown that soluble aggregation intermediates of αS, termed oligomers, permeabilize a variety of phospholipid membranes; thus, membrane disruption may represent a key pathogenic mechanism of αS toxicity. Given the centrality of mitochondrial dysfunction in PD, we therefore probed the formation of ion-permeable pores by αS oligomers in planar lipid bilayers reflecting the complex phospholipid composition of mitochondrial membranes. Using single-channel electrophysiology, we recorded distinct multi- level conductances (100-400 pS) with step-wise current transitions, typical of protein-bound nanopores, in mitochondrial-like membranes. Crucially, we observed that the presence of cardiolipin (CL), the signature phospholipid of mitochondrial membranes, enhanced αS-lipid interaction and the membrane pore-forming activity of αS oligomers. Further, pre-incubation of isolated mitochondria with a CL-specific dye protected against αS oligomer-induced mitochondrial swelling and release of cytochrome c. Hence, we favor a scenario in which αS oligomers directly porate a local lipid environment rich in CL, for instance outer mitochondrial contact sites or the inner mitochondrial membrane, to induce mitochondrial dysfunction. Pharmacological modulation of αS pore complex formation might thus preserve mitochondrial membrane integrity and alleviate mitochondrial dysfunction in PD.

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Language(s): eng - English
 Dates: 2019-07-292019
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acschemneuro.9b00320
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Title: ACS Chemical Neuroscience
Source Genre: Journal
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Pages: - Volume / Issue: 10 (8) Sequence Number: - Start / End Page: 3815 - 3829 Identifier: -