Dual Effects of Presynaptic Membrane Mimetics on α-Synuclein Amyloid Aggregation

Yuxi Lin; Dai Ito; Je Min Yoo; Mi Hee Lim; Wookyung Yu; Yasushi Kawata; Young-Ho Lee

doi:10.3389/fcell.2022.707417

Dual Effects of Presynaptic Membrane Mimetics on α-Synuclein Amyloid Aggregation

Front Cell Dev Biol. 2022 Jun 7:10:707417. doi: 10.3389/fcell.2022.707417. eCollection 2022.

Authors

Yuxi Lin^{1

2}, Dai Ito³, Je Min Yoo⁴, Mi Hee Lim⁵, Wookyung Yu^{3

6}, Yasushi Kawata⁷, Young-Ho Lee^{1

2

8

9

10}

Affiliations

¹ Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, South Korea.
² Institute for Protein Research, Osaka University, Suita, Japan.
³ Department of Brain and Cognitive Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea.
⁴ Biographene, Los Angeles, CA, United States.
⁵ Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
⁶ Core Protein Resources Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea.
⁷ Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori, Japan.
⁸ Bio-Analytical Science, University of Science and Technology, Daejeon, South Korea.
⁹ Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea.
¹⁰ Research Headquarters, Korea Brain Research Institute, Daegu, South Korea.

Abstract

Aggregation of intrinsically disordered α-synuclein (αSN) under various conditions is closely related to synucleinopathies. Although various biological membranes have shown to alter the structure and aggregation propensity of αSN, a thorough understanding of the molecular and mechanical mechanism of amyloidogenesis in membranes remains unanswered. Herein, we examined the structural changes, binding properties, and amyloidogenicity of three variations of αSN mutants under two types of liposomes, 1,2-Dioleoyl-sn-glycero-3-Phosphocholine (DOPC) and presynaptic vesicle mimetic (Mimic) membranes. While neutrally charged DOPC membranes elicited marginal changes in the structure and amyloid fibrillation of αSNs, negatively charged Mimic membranes induced dramatic helical folding and biphasic amyloid generation. At low concentration of Mimic membranes, the amyloid fibrillation of αSNs was promoted in a dose-dependent manner. However, further increases in the concentration constrained the fibrillation process. These results suggest the dual effect of Mimic membranes on regulating the amyloidogenesis of αSN, which is rationalized by the amyloidogenic structure of αSN and condensation-dilution of local αSN concentration. Finally, we propose physicochemical properties of αSN and membrane surfaces, and their propensity to drive electrostatic interactions as decisive factors of amyloidogenesis.

Keywords: Parkinson’s disease; amyloid fibril; electrostatic interaction; helical structure; intermolecular interaction; membrane mimetic; presynaptic vesicle; α-Synuclein.