Abstract
The deposition of coassemblies made of the small presynaptic protein, α-synuclein, and lipids in the brains of patients is the hallmark of Parkinson’s disease. In this study, we used natural abundance 13C and 31P magic-angle spinning nuclear magnetic resonance spectroscopy together with cryo-electron microscopy and differential scanning calorimetry to characterize the fibrils formed by α-synuclein in the presence of vesicles made of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine or 1,2-dilauroyl-sn-glycero-3-phospho-L-serine. Our results show that these lipids coassemble with α-synuclein molecules to give thin and curly amyloid fibrils. The coassembly leads to slower and more isotropic reorientation of lipid molecular segments and a decrease in both the temperature and enthalpy of the lipid chain-melting compared with those in the protein-free lipid lamellar phase. These findings provide new insights into the properties of lipids within protein–lipid assemblies that can be associated with Parkinson’s disease.
Highlights
Parkinson’s disease (PD) is characterized by the presence in the brains of patients of protein deposits known as Lewy bodies (LBs).[1]
We used natural abundance 13C and 31P magic-angle spinning nuclear magnetic resonance spectroscopy together with cryo-electron microscopy and differential scanning calorimetry to characterize the fibrils formed by α-synuclein in the presence of vesicles made of 1,2-dimyristoyl-sn-glycero-3-phospho-Lserine or 1,2-dilauroyl-sn-glycero-3-phospho-L-serine
The concentration of α-synuclein lipid-induced protofibrils formed in these experiments was found to be proportional to the concentration of the lipids (DMPS and DLPS) ([fibrils] ∼ 0.1[lipids]),[12] suggesting that lipids may be involved in the initial steps of the reaction resulting in amyloid formation[11] and act as reactants in this process
Summary
Figure 2. 13C MAS NMR spectra and dynamics of DMPS and DLPS in the pure lipid systems and within α-synuclein proto-fibrils. (A and B) 13C. 13C MAS NMR spectra and dynamics of DMPS and DLPS in the pure lipid systems and within α-synuclein proto-fibrils. CP-DP-INEPT MAS NMR spectra of the pure lipid systems (top) and of lipid-induced α-synuclein proto-fibrils (bottom) (A, DMPS; B, DLPS) measured at 60 (A) or 30◦C (B), respectively. The molecular structure of DMPS (A) and DLPS (B) molecules and the assignment of the resonances of their carbon atoms are shown above the corresponding set of spectra. 13C INEPT, CP, and DP MAS NMR spectra are shown in red, blue, and gray, respectively. The proto-fibrils were formed after mixing 100 μM monomeric α-synuclein with 2 mM DMPS (A) or DLPS (B). (C and D) Relative intensities from the INEPT and CP experiments for the pure lipid systems (top) or for the lipids incorporated within α-synuclein proto-fibrils (bottom) at °C for DMPS or
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