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Preparation and Characterization of Stable ?-Synuclein Lipoprotein Particles.


ABSTRACT: Multiple neurodegenerative diseases are caused by the aggregation of the human ?-Synuclein (?-Syn) protein. ?-Syn possesses high structural plasticity and the capability of interacting with membranes. Both features are not only essential for its physiological function but also play a role in the aggregation process. Recently it has been proposed that ?-Syn is able to form lipid-protein particles reminiscent of high-density lipoproteins. Here, we present a method to obtain a stable and homogeneous population of nanometer-sized particles composed of ?-Syn and anionic phospholipids. These particles are called ?-Syn lipoprotein (nano)particles to indicate their relationship to high-density lipoproteins formed by human apolipoproteins in vivo and of in vitro self-assembling phospholipid bilayer nanodiscs. Structural investigations of the ?-Syn lipoprotein particles by circular dichroism (CD) and magic angle solid-state nuclear magnetic resonance (MAS SS-NMR) spectroscopy establish that ?-Syn adopts a helical secondary structure within these particles. Based on cryo-electron microscopy (cryo-EM) and dynamic light scattering (DLS) ?-Syn lipoprotein particles have a defined size with a diameter of ?23 nm. Chemical cross-linking in combination with solution-state NMR and multiangle static light scattering (MALS) of ?-Syn particles reveal a high-order protein-lipid entity composed of ?8-10 ?-Syn molecules. The close resemblance in size between cross-linked in vitro-derived ?-Syn lipoprotein particles and a cross-linked species of endogenous ?-Syn from SH-SY5Y human neuroblastoma cells indicates a potential functional relevance of ?-Syn lipoprotein nanoparticles.

SUBMITTER: Eichmann C 

PROVIDER: S-EPMC4861424 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Multiple neurodegenerative diseases are caused by the aggregation of the human α-Synuclein (α-Syn) protein. α-Syn possesses high structural plasticity and the capability of interacting with membranes. Both features are not only essential for its physiological function but also play a role in the aggregation process. Recently it has been proposed that α-Syn is able to form lipid-protein particles reminiscent of high-density lipoproteins. Here, we present a method to obtain a stable and homogeneou  ...[more]

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