Molecular Role of Ca2+ and Hard Divalent Metal Cations on Accelerated Fibrillation and Interfibrillar Aggregation of \u03b1-Synuclein

Jong Yoon Han,Hugh I Kim,Tae Su Choi

doi:10.1038/s41598-018-20320-5

Jong Yoon Han, Hugh I Kim + Show 1 more

Open Access

https://doi.org/10.1038/s41598-018-20320-5

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Journal: Scientific Reports	Publication Date: Jan 30, 2018
Citations: 46	License type: open-access

Affiliation: Korea University

Abstract

α-Synuclein (αSyn) is an intrinsically disordered protein, the aggregation of which is highly related to the pathology of diverse α-synucleinopathies. Various hard divalent metal cations have been shown to affect αSyn aggregation. Especially, Ca2+ is suggested to be a crucial ion due to its physiological relevance to α-synucleinopathies. However, the molecular origin of αSyn aggregation mediated by the metal ions is not fully elucidated. In this study, we revealed that hard divalent metal ions had almost identical influences on αSyn aggregation. Based on these similarities, the molecular role of Ca2+ was investigated as a representative metal ion. Herein, we demonstrated that binding of multiple Ca2+ ions induces structural transition of αSyn monomers to extended conformations, which promotes rapid αSyn fibrillation. Additionally, we observed that Ca2+ induced further interfibrillar aggregation via electrostatic and hydrophobic interactions. Our results from multiple biophysical methods, including ion mobility-mass spectrometry (IM-MS), synchrotron small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), provide detailed information on the structural change of αSyn and the aggregation process mediated by Ca2+. Overall, our study would be valuable for understanding the influence of Ca2+ on the aggregation of αSyn during the pathogenesis of α-synucleinopathies.

Highlights

Α-Synuclein is a small amyloidogenic protein, which is abundant, at the presynaptic nerve terminals5–7. αSyn is considered to modulate the synaptic vesicle cycle, which is involved in neurotransmission[7,8]; it has received attention because of its pathological significance as the main component of Lewy bodies and Lewy neurites, observed in patients with α-synucleinopathies such as Parkinson’s disease (PD), multiple system atrophy (MSA), and Lewy body dementia (LBD)9. αSyn is an intrinsically disordered protein (IDP), and comprises 140 amino acid residues, which constitute the amphipathic domain at the N-terminal region, the hydrophobic non-amyloid-β component (NAC) region, and the acidic domain at the C-terminal region (Fig. 1A)
Our structural and kinetic results, which were obtained using multiple biophysical methods, including ion mobility-mass spectrometry (IM-MS), transmission electron microscopy (TEM), synchrotron small-angle X-ray scattering (SAXS), and inductively coupled plasma optical emission spectroscopy (ICP-OES) demonstrated that Ca2+ mediates the rapid formation of αSyn fibrils via the structural transition of monomeric αSyn into an extended conformation, which is prone to aggregation
Our results demonstrated that multiple Ca2+ ions bound to the C-terminal region of αSyn stimulates the structural transition of αSyn monomers that exposes the NAC region

Summary

Introduction

We demonstrated that binding of multiple Ca2+ ions induces structural transition of αSyn monomers to extended conformations, which promotes rapid αSyn fibrillation. The mechanism of αSyn aggregation mediated by Ca2+, a representative hard divalent cation, was proposed by monitoring the structural transition of αSyn from the monomeric state to the large interfibrillar aggregate state.

Results

Conclusion