Comparing α-Synuclein Fibrils Formed in the Absence and Presence of a Model Lipid Membrane: A Small and Wide-Angle X-Ray Scattering Study

Ulf Olsson,Sara Linse,Emma Sparr,Marija Dubackic

doi:10.3389/frsfm.2021.741996

Abstract

Amyloid fibrils are associated with a number of different neurodegenerative diseases. Detailed knowledge of the fibril structure will be of importance in the search of therapy and may guide experiments to understand amyloid formation. In this paper we investigate the morphology of α-synuclein amyloid fibrils, associated with Parkinson’s disease, formed under different conditions. In particular, we study, by means of small and wide-angle X-ray scattering, whether the presence of model lipid membranes affect the overall structure of the fibrils formed, motivated by the fact that amyloid fibrils in vivo are formed in a highly lipid-rich environment. Comparing fibrils formed in the presence of lipid with fibrils formed in their absence, show that the presence of lipids has no detectable effect on the fibril cross-section radius and that the characteristic β-strand repeat distance of 4.7 Å of the extended intermolecular β-sheets remains unaffected. We also show that the observed fibril radius is consistent with a fibril structure composed of two protofilaments. This indicates overall that the particular fibril structure, with their stacks of two-dimensionally folded α-synuclein molecules, represent a deep free energy minimum, not largely affected by the co-aggregation with lipids.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 0.3% of world’s population (von Campenhausen et al, 2005)
Multiple lines of evidence indicate that the formation of amyloid aggregates, present in so-called Lewy bodies, or the intermediate oligomeric aggregates present during the course of the aggregation process, are toxic to dopaminergic neurons and contributes to degeneration in PD (Bucciantini et al, 2002; Winner et al, 2011; Iyer and Claessens, 2018; Ke et al, 2020; Melo et al, 2021)
A major component of Lewy bodies are fibrils formed by the protein α-synuclein, αS (Baba et al, 1998; Araki et al, 2019), a 140 amino acid-long protein abundantly expressed in neuronal cells and located in the

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 0.3% of world’s population (von Campenhausen et al, 2005). This movement disorder is marked by a loss of dopaminergic neurons in a midbrain region, substantia nigra (Anichtchik et al, 2000; Lehericy et al, 2014). Symptoms of PD such as rigor, tremor and slowed motions (bradykinesia) (Fahn, 2003) may be ameliorated, the disease remains without cure. The clinically manifested symptoms do not present themselves before 80% of dopamine signaling have been lost (Fearnley and Lees, 1991). A major component of Lewy bodies are fibrils formed by the protein α-synuclein, αS (Baba et al, 1998; Araki et al, 2019), a 140 amino acid-long protein abundantly expressed in neuronal cells and located in the

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