Dataset Information

Interactions between Soluble Species of ?-Amyloid and ?-Synuclein Promote Oligomerization while Inhibiting Fibrillization.

ABSTRACT: Aggregations of ?-amyloid (A?) and ?-synuclein (?S) into oligomeric and fibrillar assemblies are the pathological hallmarks of Alzheimer's and Parkinson's diseases, respectively. Although A? and ?S affect different regions of the brain and are separated at the cellular level, there is evidence of their eventual interaction in the pathology of both disorders. Characterization of interactions of A? and ?S at various stages of their aggregation pathways could reveal mechanisms and therapeutic targets for the prevention and cure of these neurodegenerative diseases. In this study, we comprehensively examined the interactions and their molecular manifestations using an array of characterization tools. We show for the first time that ?S monomers and oligomers, but not ?S fibrils, inhibit A? fibrillization while promoting oligomerization of A? monomers and stabilizing preformed A? oligomers via coassembly, as judged by Thioflavin T fluorescence, transmission electron microscopy, and SDS- and native-PAGE with fluorescently labeled peptides/proteins. In contrast, soluble A? species, such as monomers and oligomers, aggregate into fibrils, when incubated alone under the otherwise same condition. Our study provides evidence that the interactions with ?S soluble species, responsible for the effects, are mediated primarily by the C-terminus of A?, when judged by competitive immunoassays using antibodies recognizing various fragments of A?. We also show that the C-terminus of A? is a primary site for its interaction with ?S fibrils. Collectively, these data demonstrate aggregation state-specific interactions between ?S and A? and offer insight into a molecular basis of synergistic biological effects between the two polypeptides.

SUBMITTER: Candreva J

PROVIDER: S-EPMC7269195 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization.

Candreva Jason J Chau Edward E Rice Margaret E ME Kim Jin Ryoun JR

Biochemistry 20191230 4

Aggregations of β-amyloid (Aβ) and α-synuclein (αS) into oligomeric and fibrillar assemblies are the pathological hallmarks of Alzheimer's and Parkinson's diseases, respectively. Although Aβ and αS affect different regions of the brain and are separated at the cellular level, there is evidence of their eventual interaction in the pathology of both disorders. Characterization of interactions of Aβ and αS at various stages of their aggregation pathways could reveal mechanisms and therapeutic targe ...[more]

PMID: 31854188

Similar Datasets

Project description:The chemical and physical mechanisms by which gyrating beads accelerate amyloid fibrillization in microtiter plate assays are unclear. Identifying these mechanisms will help optimize high-throughput screening assays for molecules and mutations that modulate aggregation and might explain why different research groups report different rates of aggregation for identical proteins. This article investigates how the rate of superoxide dismutase-1 (SOD1) fibrillization is affected by 12 different beads with a wide range of hydrophobicity, mass, stiffness, and topology but identical diameter. All assays were performed on D90A apo-SOD1, which is a stable and wild-type-like variant of SOD1. The most significant and uniform correlation between any material property of each bead and that bead's effect on SOD1 fibrillization rate was with regard to bead mass. A linear correlation existed between bead mass and rate of fibril elongation (R2 = 0.7): heavier beads produced faster rates and shorter fibrils. Nucleation rates (lag time) also correlated with bead mass, but only for non-polymeric beads (i.e., glass, ceramic, metallic). The effect of bead mass on fibrillization correlated (R2 = 0.96) with variations in buoyant forces and contact forces (between bead and microplate well), and was not an artifact of residual momentum during intermittent gyration. Hydrophobic effects were observed, but only for polymeric beads: lag times correlated negatively with contact angle of water and degree of protein adhesion (surface adhesion and hydrophobic effects were negligible for non-polymeric beads). These results demonstrate that contact forces (alone) explain kinetic variation among non-polymeric beads, whereas surface hydrophobicity and contact forces explain kinetic variation among polymeric beads. This study also establishes conditions for high-throughput amyloid assays of SOD1 that enable the control over fibril morphologies and produce eightfold faster lag times and fourfold less stochasticity than in previous studies.

Dataset Information

Interactions between Soluble Species of ?-Amyloid and ?-Synuclein Promote Oligomerization while Inhibiting Fibrillization.

Publications

Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets