title: Small-angle neutron scattering reveals the assembly of alpha-synuclein in lipid membranes.
abstract: The aggregation of α-synuclein (asyn), an intrinsically disordered protein (IDP), is a hallmark in Parkinson's disease (PD). We investigated the conformational changes that asyn undergoes in the presence of membrane and membrane mimetics using small-angle neutron scattering (SANS). In solution, asyn is monomeric and unfolded assuming an ensemble of conformers spanning extended and compact conformations. Using the contrast variation technique and SANS, the protein scattering signal in the membrane-protein complexes is selectively highlighted in order to monitor its conformational changes in this environment. We showed that in the presence of phospholipid membranes asyn transitions from a monodisperse state to aggregated structures with sizes ranging from 200 to 900Å coexisting with the monomeric species. Detailed SANS data analysis revealed that asyn aggregates have a hierarchical organization in which clusters of smaller asyn aggregates assemble to form the larger structures. This study provides new insight into the mechanism of asyn aggregation. We propose an aggregation mechanism in which stable asyn aggregates seed the aggregation process and hence the hierarchical assembly of structures. Our findings demonstrate that membrane-induced conformational changes in asyn lead to its heterogeneous aggregation which could be physiologically relevant in its function or in the diseased state.
authors: Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States.
authors: Divina
authors: D
authors: Anunciado
authors: Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States.
authors: Durgesh K
authors: DK
authors: Rai
authors: Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States.
authors: Shuo
authors: S
authors: Qian
authors: Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States.
authors: Volker
authors: V
authors: Urban
authors: Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, United States.
authors: Hugh
authors: H
authors: O'Neill
mesh_terms: D008563:Membrane Lipids / Q000378:metabolism*; D009502:Neutrons; D012542:Scattering, Radiation; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D008563:Membrane Lipids; D051844:alpha-Synuclein
keywords: Aggregation; Alpha-synuclein; Hierarchical structure; Lipid membrane; Parkinson’s disease; Small-angle scattering