College 8 Seminar | Membrane interactions of the pore-forming α-synuclein oligomer

Seminar room 110-111, ILL 50, 1st floor

Zoom Link

https://ill.zoom.us/j/93819944809

Meeting ID: 938 1994 4809

Aggregates of the protein α-synuclein (αSyn) are widely regarded as the pathological hallmark of a group of neurogenerative diseases called synucleinopathies, which include Parkinson’s disease. In its monomeric form, αSyn performs a wide range of functions at nerve terminals, for which its ability to bind membranes is essential. In contrast, oligomers of αSyn are increasingly recognised as key toxic species in the pathogenesis of Parkinson’s disease, yet the structural basis of their membrane interactions poorly defined. Compared with monomers and fibrils, αSyn oligomers reportedly have a higher tendency to insert into lipid bilayers, disrupt the membrane, and cause the formation of pores, which may underlie their increased toxicity. Lipid composition strongly influences oligomer recruitment, insertion, and pore formation, but the depth and mode of membrane penetration have not yet been resolved at sub-nanometre scale. Here, we seek to use neutron reflectometry (NR) of supported lipid bilayers (SLBs), in conjunction with quartz crystal microbalance with dissipation (QCM-D) measurements of both SLBs and free-floating bilayers (FFBs), and small-angle X-ray scattering (SAXS) to determine how lipid properties modulate αSyn oligomer-membrane interactions. We aim to quantify oligomer binding, insertion depth, and structural rearrangements and compare these with both monomeric and fibrillar αSyn. Our aim is to establish a mechanistic framework for how αSyn oligomers disrupt membranes, which may ultimately identify lipid-dependent features to guide therapeutic strategies.

by Katherine Dewison | Aarhus University, Denmark

Sophie Ayscough (College 8 Secretary)

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