title: Preparation and Characterization of Stable α-Synuclein Lipoprotein Particles.
abstract: 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 homogeneous population of nanometer-sized particles composed of α-Syn and anionic phospholipids. These particles are called α-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 α-Syn lipoprotein particles by circular dichroism (CD) and magic angle solid-state nuclear magnetic resonance (MAS SS-NMR) spectroscopy establish that α-Syn adopts a helical secondary structure within these particles. Based on cryo-electron microscopy (cryo-EM) and dynamic light scattering (DLS) α-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 α-Syn particles reveal a high-order protein-lipid entity composed of ∼8-10 α-Syn molecules. The close resemblance in size between cross-linked in vitro-derived α-Syn lipoprotein particles and a cross-linked species of endogenous α-Syn from SH-SY5Y human neuroblastoma cells indicates a potential functional relevance of α-Syn lipoprotein nanoparticles.
authors: From the Laboratory of Physical Chemistry and.
authors: Cédric
authors: C
authors: Eichmann
authors: From the Laboratory of Physical Chemistry and.
authors: Silvia
authors: S
authors: Campioni
authors: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors: Julia
authors: J
authors: Kowal
authors: Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037 and.
authors: Innokentiy
authors: I
authors: Maslennikov
authors: Institute of Biochemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
authors: Juan
authors: J
authors: Gerez
authors: Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors: Xiaoxia
authors: X
authors: Liu
authors: From the Laboratory of Physical Chemistry and.
authors: Joeri
authors: J
authors: Verasdonck
authors: From the Laboratory of Physical Chemistry and.
authors: Nadezhda
authors: N
authors: Nespovitaya
authors: Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037 and.
authors: Senyon
authors: S
authors: Choe
authors: From the Laboratory of Physical Chemistry and.
authors: Beat H
authors: BH
authors: Meier
authors: Institute of Biochemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
authors: Paola
authors: P
authors: Picotti
authors: Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors: Josep
authors: J
authors: Rizo
authors: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors: Henning
authors: H
authors: Stahlberg
authors: From the Laboratory of Physical Chemistry and Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037 and roland.riek@phys.chem.ethz.ch.
authors: Roland
authors: R
authors: Riek
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010743:Phospholipids / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D008075:Lipoproteins, HDL; D010743:Phospholipids; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Parkinson disease; alpha-synuclein (α-synuclein); apolipoprotein; high-density lipoprotein (HDL); lipid; membrane bilayer