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bioRxiv · 10.1101/2023.03.21.533646

Alpha-synuclein oligomers displace monomeric alpha-synuclein from lipid membranes

Sneideriene, G.·Czekalska, M. A.·Xu, C. K.·Jayaram, A.·Krainer, G.·Arter, W. E.·Peter, Q.·Castellana-Cruz, M.·Saar, K. L.·Levin, A.·Mueller, T.·Fiedler, S.·Devenish, S. R. A.·Fiegler, H.·Kumita, J. R.·Knowles, T.
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Abstract

Parkinsons disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of -synuclein (S) protein aggregates in the nervous system. While S binding to membranes in its monomeric state is correlated to its physiological role, S oligomerisation and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric S (OS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OS-membrane interactions. We find that OS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OS and monomeric S (MS), we further demonstrate that OS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OS compete with and displace bound MS from the membrane surface, suggesting that disruption to the functional binding of MS to membranes may provide an additional toxicity mechanism in PD. These findings present a unique binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/533646v2_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@4ab089org.highwire.dtl.DTLVardef@18c0709org.highwire.dtl.DTLVardef@220077org.highwire.dtl.DTLVardef@4c85b9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sneideriene, G., Czekalska, M. A., Xu, C. K., Jayaram, A., Krainer, G., Arter, W. E., Peter, Q., Castellana-Cruz, M., Saar, K. L., Levin, A., Mueller, T., Fiedler, S., Devenish, S. R. A., Fiegler, H., Kumita, J. R., Knowles, T.. 2023-03-21. Alpha-synuclein oligomers displace monomeric alpha-synuclein from lipid membranes. https://doi.org/10.1101/2023.03.21.533646

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