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.2019 Dec 19;10(24):7872-7877.
doi: 10.1021/acs.jpclett.9b03005. Epub 2019 Dec 6.

Lipid Dynamics and Phase Transition within α-Synuclein Amyloid Fibrils

Affiliations

Lipid Dynamics and Phase Transition within α-Synuclein Amyloid Fibrils

Céline Galvagnion et al. J Phys Chem Lett..

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 abundance13C and31P 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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Cryo-EMimages of proto-fibrils formed by α-synuclein inthe presence of DMPS and DLPS vesicles. The proto-fibrils were formedafter mixing 50 μM monomeric α-synuclein with 100 μMDMPS (A) or DLPS (B) dispersed as small unilamellar vesicles in phosphatebuffer at pH 6.5 and 30 °C and incubating this mixture for 4d under quiescent conditions (see Methods in theSupporting Information for more details).
Figure 2
Figure 2
13C MAS NMR spectra and dynamics of DMPS and DLPS inthe pure lipid systems and within α-synuclein proto-fibrils.(A and B)13C CP-DP-INEPT MAS NMR spectra of the pure lipidsystems (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 carbonatoms 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 μMmonomeric α-synuclein with 2 mM DMPS (A) or DLPS (B) dispersedas small unilamellar vesicles in phosphate buffer at pH 6.5 and 30°C and incubating this mixture for 4 d under quiescent conditions.(C and D) Relative intensities from the INEPT and CP experiments forthe pure lipid systems (top) or for the lipids incorporated withinα-synuclein proto-fibrils (bottom) at 60 °C for DMPS or30 °C for DLPS. The ratioformula image depends on both the correlation time, τC, and the order parameter, |SCH|, for the C–Hbond vector in the molecular segment; the relative value for eachcarbon atom is displayed using the color scheme shown at the bottomof the figure.
Figure 3
Figure 3
31P MAS NMR spectra, chemical shift anisotropy, andDSC thermograms of DMPS in the pure lipid system and within α-synucleinproto-fibrils. (A)31P MAS NMR spectra at spinning rate= 1250 Hz of pure DMPS (top) and DMPS-induced α-synuclein proto-fibrils(bottom) measured at 60 °C. The experimental data are shown ascontinuous lines; the fits are shown as dotted black lines, and theresiduals of the fits are shown underneath each spectrum. (B) Combinedresults from31P MAS NMR and DSC measurements for DMPSin the pure lipid system and within α-synuclein proto-fibrilsat varying temperatures. Lefty-axis: Change in the31P Δσ of the pure DMPS (blue circles) and DMPS-inducedα-synuclein proto-fibrils (purple squares) with increasing temperatures.Righty-axis: Change in the molar heat capacity (Cp)of DMPS solubilized as vesicles (blue dashed line) or of DMPS-inducedα-synuclein proto-fibrils untreated (purple dashed line) ortreated with proteinase-K (black dashed line) with increasing temperatures.The chain melting enthalpies were found to be ca. 25 (pure lipid system,blue dashed line), ca. 6 kJ mol–1 (DMPS-inducedα-synuclein proto-fibrils, purple dashed line) and ca. 17 kJmol–1 (proteinase-K treated DMPS-induced α-synucleinproto-fibrils, black dashed line).
Figure 4
Figure 4
Illustration of the influence of the coassembly of DMPSand α-synucleinwithin proto-fibrils on the lipid dynamics measured at 60 °C.Theoretical1H–13C polarization transferefficiency as a function of τC and |SCH| for a CH2 segment at the magnetic field 11.7 T and themagic-angle spinning frequency 5 kHz (adapted from ref (20) with permission; copyright2013 Elsevier). The map is color-coded according to the calculatedCP (blue) and INEPT (red) intensities. White indicates the absenceof signal for both CP and INEPT. Each circle corresponds to a carbonof the acyl chain (C2–C14) of DMPS inthe pure lipid system (white open circles) or in the protein–lipidproto-fibrils (black open circles). The position of the carbons resultsfrom the estimations of τC and |SCH| thatare based on previous quantitative measurements of those parameters, (Pure DMPS: |SCH| (C2–C6) ≈ 0.2, |SCH| (C6–C13): 0.2 to 0.05, |SCH| (C14) ≈ 0.01,τC (C2–C13): 1–0.1ns, τC (C14) ≈ 0.01 ns; DMPS inα-synuclein proto-fibrils: τC increased forall carbons by approximately a factor of 100,, and |SCH| decreased for all carbons by a factor of ∼1.3(see Figure 3B)).
Figure 5
Figure 5
13C MAS NMR spectra of DMPS in purelipid systems andwithin α-synuclein proto-fibrils at different temperatures.(A and B)13C CP-DP-INEPT MAS NMR spectra of the pure DMPS(A) or DMPS-induced α-synuclein proto-fibrils (B) measured atincreasing temperatures encompassing the melting temperature of DMPSbilayer (Tm ≈ 39 °C). The molecular structure of DMPS molecules as well as the assignmentof the resonances of their carbon atoms are shown above the correspondingset of spectra.13C INEPT, CP, and DP MAS NMR spectra areshown in red, blue, and gray, respectively. The dotted lines labeledG (gel) and F (fluid) indicate the chemical shift of the unresolvedresonances of the acyl C4–C11 carbonswhen the lipid chains adopt all-trans ortrans–gauche conformation, respectively.
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