α-Synuclein lipoprotein nanoparticles

Cédric Eichmann; Stefan Bibow; Roland Riek

doi:10.1515/ntrev-2016-0062

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α-Synuclein lipoprotein nanoparticles

Cédric Eichmann , Stefan Bibow and Roland Riek

Published/Copyright: January 20, 2017

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From the journal Nanotechnology Reviews Volume 6 Issue 1

Abstract

Apolipoprotein nanodiscs are a versatile tool in nanotechnology as membrane mimetics allowing, for example, the study of membrane proteins. It has recently been discovered that the Parkinson’s disease associated protein α-synuclein (α-Syn) can also form discoid-like lipoprotein nanoparticles. The present review highlights the observation that α-Syn has the properties to define stable and homogeneous populations of nanoparticles with diameters of 7–10 nm and 19–28 nm by modifying lipid vesicles or encapsulating lipid bilayers in a nanodisc-type fashion, respectively. In contrast to apolipoprotein nanodiscs, α-Syn nanoparticles can incorporate entirely negatively charged lipids emphasizing their potential use in nanotechnology as a negatively charged membrane mimetic.

Keywords: lipoprotein; nanodiscs; NMR; Parkinson’s disease; α-synuclein

1 Introduction

The protein α-synuclein (α-Syn) is associated with Parkinson’s disease (PD) [1], [2]. Its conformational plasticity appears to be of key importance for the physiological functions. Whereas monomeric α-Syn is largely disordered [3], [4], [5] in an aqueous solution, membrane mimicking environments containing anionic detergents [3] or phospholipids [5], [6], [7] trigger a disorder-to-helix transition. The structural transition towards an α-helical state is mediated by seven imperfect 11 amino acid long amphipathic repeats in the N-terminal region of α-Syn that bear resemblance to the amphipathic helical repeats found in apolipoproteins [3], [6], [8]. Notably, the C-terminal residues remain unstructured during in vitro experiments since they do not seem to interact with anionic membranes [5], [9]. Still highly debated is the in vivo structure of α-Syn. In 2011, two groups reported that cellular α-Syn exists as a helical tetramer when purified under non-denaturing conditions [10], [11]. However, these results were recently challenged by in-cell nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) studies of α-Syn electroporated into mammalian cells [12]. The in-cell NMR spectra showed protein signals that overlapped with those NMR signals observed for disordered in vitro α-Syn, therefore excluding the possibility of a major tetrameric folded species under these experimental conditions [12], [13].

A structure-function relationship has not yet been established because the physiological role of α-Syn is still unknown [14], [15], [16]. There is, however, growing evidence that α-Syn-membrane interactions form the basis of multiple in vivo functions such as synaptic vesicle pool maintenance [17], [18], regulation of dopamine neurotransmission [19], [20], transport of lipids and fatty acids [21], [22], [23], [24], [25], membrane trafficking [26], [27], [28], synaptic plasticity [29], [30], and assistance in SNARE complex formation [31], [32], [33], [34]. Moreover, membranes also seem to influence the pathological aggregation of α-Syn towards amyloid fibrils with β-sheet structure, the hallmark of PD [35], [36], [37], [38], [39], [40], [41], [42], [43]. Although the physiological function(s) of α-Syn remain elusive, the seven imperfect 11 amino acid long amphipathic repeats in the N-terminal region of α-Syn and their capability to interact both with negatively charged and zwitterionic phospholipids allows for the in vitro formation of discoid-like lipoprotein nanoparticles, so-called α-Syn lipoprotein nanoparticles [44], [45], [46]. These α-Syn lipoprotein nanoparticles are the focus of this review with an emphasis on their potential use in nanotechnology as a membrane container comprising negatively charged lipids or a membrane mimetic for the study of membrane proteins with properties distinct from the usually used apolipoprotein nanodiscs.

2 Formation of stable α-synuclein lipoprotein particles

Incubation of monomeric α-Syn with preformed negatively charged lipid vesicles at high protein-to-lipid ratios (1:10 and higher) results in reshaping of negatively charged giant lipid vesicles and small unilamellar vesicles (SUVs, diameter ~25 nm) into discoid-like lipoprotein nanoparticles with a diameter of 7–10 nm [44], [45]. Interestingly, incubation of α-Syn with multilamellar vesicles composed of lipids commonly used to mimic mitochondrial membranes leads to a disruption of the vesicles and subsequent formation of lipid nanoparticles, indicating a link between overexpressed α-Syn and loss of mitochondrial membrane integrity [45]. In these particles the protein-to-lipid molar mass ratio is found to be in the range of 1:1.4 (protein-to-lipid molar ratio of 1:20–25), and EPR data show that α-Syn adopts a broken helical state with a partially disordered second helix [45]. Notably, this approach does not allow the formation of α-Syn nanoparticles with zwitterionic phosphatidylcholine-containing vesicles [45].

Recently, another method was established to generate α-Syn lipoprotein nanoparticles with negatively charged as well as zwitterionic phospholipids using a low protein-to-lipid ratio of 1:40 [46]. Mixing 500 μm α-Syn with 2 mm of the desired lipids dissolved in sodium cholate followed by detergent removal results in the formation of discoid-like α-Syn lipid nanoparticles of 19–28 nm diameter. A protein-to-lipid ratio higher than 1:40 leads to residual amounts of free monomeric α-Syn when incubated with negatively charged lipids. Importantly, using the nanodisc approach with the same protein-to-lipid ratio, stable α-Syn lipoprotein particles of similar size can also be formed in the presence of the natural zwitterionic lipid sphingomyelin. Remaining residual amount of monomeric α-Syn in the latter sample preparation, as evidenced by size exclusion chromatography, indicates that the α-Syn-derived lipoprotein particles with negatively charged lipids are more stable than particles comprising zwitterionic lipids (Figure 1A). The circular dichroism (CD) spectrum of α-Syn 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (DOPS) lipoprotein particles (Figure 1B) shows the characteristics of α-helical proteins, with two negative [Θ]_MRW peaks at ~210 and 221 nm, respectively, and one positive [Θ]_MRW peak at ~195 nm, resembling CD spectra of α-Syn bound to anionic lipid vesicles and anionic detergents [3], [5], [6].

Figure 1:

Structural characterization of α-Syn lipoprotein particles. (A) Size-exclusion gel chromatography (Superdex 200 10/300GL) of α-Syn DOPS (black), α-Syn POPS (green), and α-Syn sphingomyelin (red) lipoprotein particles. Monomeric (gray) α-Syn elutes at ~14.3 ml. (B) CD indicates that α-Syn adopts a helical secondary structure within α-Syn DOPS lipoprotein particles. (C) Cryo-electron microscopy images (top and side view) of α-Syn DOPS lipoprotein particles. (D) Solution state NMR shows that the ~40 C-terminal residues of α-Syn are flexible in α-Syn DOPS lipoprotein particles (red). Figure adapted from ref. [46].

Cryo-electron microscopy images of these α-Syn lipoprotein nanoparticles show a low-density inner region (~10 nm) attributed to the lipid bilayer, which is surrounded by a 6–7 nm wide higher density belt of α-Syn molecules (Figure 1C) [46]. Similar to the architecture of lipoprotein particles formed by the apolipoprotein A-1 (ApoA-1) [47], [48], [49], the higher density features at the periphery of the discs are compatible with the interpretation that α-Syn molecules are wrapped around the lipids in a ring-like manner. The core structure of these particles is formed by the first ~100 amino acid residues of α-Syn in a helical conformation (Figure 1B), while ~40 C-terminal residues remain flexible and do not interact with the lipid bilayer (Figure 1D) [45], [46], as previously documented for α-Syn in the presence of sodium dodecyl sulfate micelles or SUVs containing anionic phospholipids [5], [9].

An exact mass and composition determination of the α-Syn DOPS lipoprotein particles using size exclusion coupled multiangle static light scattering (MALS) combined with refraction index measurements indicates a total molecular weight of ~982 kDa for the α-Syn-lipid entity, ~865 kDa for the DOPS lipids, and ~116 kDa for the protein component (Figure 2A). Moreover, chemical cross-linking experiments with the disuccinimidyl glutarate (DSG, spacer length 7.7 Å) linker show at higher DSG concentration a predominant single ~150 kDa species (Figure 2B). These findings suggest that α-Syn DOPS lipoprotein particles are composed of approximately 8–10 α-Syn and ~1070 DOPS molecules with a protein-to-lipid molar mass ratio of ~1:8–10 [46] in line with theoretical calculations following a procedure established for membrane scaffold protein (MSP) nanodiscs [50]. By comparison, ~160 lipid molecules are observed in nanodiscs made of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and two copies of the protein MSP1D1 (Table 1), a truncated version of ApoA-1 [47], [48], [49], [50], [51], [52]. In contrast to α-Syn lipoprotein nanoparticles, fully negatively charged lipids cannot be incorporated into MSP nanodiscs (Table 1).

$Figure 2: Protein-lipid composition of α-Syn lipoprotein particles. (A) Molecular weight analysis of the α-Syn DOPS lipoprotein complex by MALS coupled with size-exclusion gel chromatography and refractive index measurements. The black line corresponds to the static light scattering signal at 454 nm of DABMI-labeled α-Syn(C141) in the presence of DOPS lipids; red, blue, and green lines show average molar masses of the complex, the lipid component, and the protein component in the lipoprotein particle, respectively. Following these investigations, the protein mass is ~116 kDa indicating that α-Syn is of octameric nature in DOPS lipoprotein particles. (B) Cross-linking studies of α-Syn DOPS lipoprotein particles. Lane 1, molecular weight marker (MW, SeeBlue plus2 prestained standard, Invitrogen). Lanes 2–4, cross-linked α-Syn DOPS lipoprotein particles (final concentration 83 μm) with increasing concentrations of DSG as indicated. Presumed α-Syn monomer and oligomers are indicated by arrowheads. Figure adapted from ref. [46].$

Figure 2:

Protein-lipid composition of α-Syn lipoprotein particles. (A) Molecular weight analysis of the α-Syn DOPS lipoprotein complex by MALS coupled with size-exclusion gel chromatography and refractive index measurements. The black line corresponds to the static light scattering signal at 454 nm of DABMI-labeled α-Syn(C141) in the presence of DOPS lipids; red, blue, and green lines show average molar masses of the complex, the lipid component, and the protein component in the lipoprotein particle, respectively. Following these investigations, the protein mass is ~116 kDa indicating that α-Syn is of octameric nature in DOPS lipoprotein particles. (B) Cross-linking studies of α-Syn DOPS lipoprotein particles. Lane 1, molecular weight marker (MW, SeeBlue plus2 prestained standard, Invitrogen). Lanes 2–4, cross-linked α-Syn DOPS lipoprotein particles (final concentration 83 μm) with increasing concentrations of DSG as indicated. Presumed α-Syn monomer and oligomers are indicated by arrowheads. Figure adapted from ref. [46].

Table 1:

Properties of α-Syn lipoprotein particles and MSP nanodiscs [45], [46], [47], [51], [52].

	Protein
	α-Syn	α-Syn	MSPΔH5	MSP1D1
Notes	Formation using MSP nanodisc approach	Formation using preformed lipid vesicles	Truncated version of MSP1D1, deletion of residues 121–142 (helix 5)	Residues 44–243 from ApoA-1
Zwitterionic lipids	Yes	No	Yes	Yes
Negatively charged lipids	Yes	Yes	Partly^a	Partly^a
Positively charged lipids	No	No	–	–

	Nanodisc type
	α-Syn DOPS	α-Syn POPG	MSPΔH5 DMPC	MSP1D1 DMPC
Number of proteins	8–10	3–4	2	2
Number of lipids	1070	80–100	100	160
Diameter	19–28 nm	7–10 nm	8.4 nm	9.5 nm
Molecular weight	982 kDa	135 kDa	108 kDa	158 kDa
Protein-to-lipid molar mass ratio	1:8	1:1.4	1:1.7	1:2.5

^aFrom our experience, loading the nanodiscs with 100% negatively charged lipids results in highly unstable nanodiscs, whereas a composition of 33% negatively charged lipids with 66% zwitterionic lipids yields stable nanodiscs.

3 Biophysical and physiological relevance of α-synuclein lipoprotein nanoparticles

The apolipoprotein-like lipid-binding capabilities, sequence similarities to apolipoproteins, and the seven imperfect 11 amino acid long amphipathic repeats stimulated the speculation that α-Syn might be capable of forming lipid-protein nanoparticles, but only recent studies confirmed these speculations with experimental evidence as discussed above [44], [45], [46].

From a biological point of view, α-Syn nanoparticles might be involved in lipid transport and storage [45], [46]. The reviewed in vitro reconstitution of α-Syn nanoparticles may allow to test, under experimentally controlled conditions, whether and how α-Syn nanoparticles are involved in lipid transport, lipid metabolism with the help of (unknown) enzymes, synaptic plasticity, synaptic vesicle pool maintenance, SNARE complex formation or mitochondrial membrane disruption, etc.

From a biophysical perspective, α-Syn lipoprotein particles may serve as a complementary tool to study membrane proteins in a native-like bilayer environment since α-Syn lipoprotein particles allow the incorporation of negatively charged lipids that are incompatible with other self-assembling lipid bilayer nanodiscs.

Acknowledgments

This work was supported by a Swiss National Science Foundation (SNSF) Grant/Award Number: “154461 and 160979” Sinergia grant and the SNSF grant P300PA_160979 to C.E.

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Received: 2016-7-28

Accepted: 2016-11-12

Published Online: 2017-1-20

Published in Print: 2017-2-1

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https://doi.org/10.1515/ntrev-2016-0062

Keywords for this article

lipoprotein; nanodiscs; NMR; Parkinson’s disease; α-synuclein

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