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. 2013 Mar 1:4:17.
doi: 10.3389/fneur.2013.00017. eCollection 2013.

Biophysical insights into how surfaces, including lipid membranes, modulate protein aggregation related to neurodegeneration

Kathleen A Burke  1 , Elizabeth A Yates, Justin Legleiter
Affiliations

Biophysical insights into how surfaces, including lipid membranes, modulate protein aggregation related to neurodegeneration

Kathleen A Burke et al. Front Neurol. .

Abstract

There are a vast number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), associated with the rearrangement of specific proteins to non-native conformations that promotes aggregation and deposition within tissues and/or cellular compartments. These diseases are commonly classified as protein-misfolding or amyloid diseases. The interaction of these proteins with liquid/surface interfaces is a fundamental phenomenon with potential implications for protein-misfolding diseases. Kinetic and thermodynamic studies indicate that significant conformational changes can be induced in proteins encountering surfaces, which can play a critical role in nucleating aggregate formation or stabilizing specific aggregation states. Surfaces of particular interest in neurodegenerative diseases are cellular and subcellular membranes that are predominately comprised of lipid components. The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions. Importantly for misfolding diseases, these bilayer properties can not only modulate protein conformation, but also exert influence on aggregation state. A detailed understanding of the influence of (sub)cellular surfaces in driving protein aggregation and/or stabilizing specific aggregate forms could provide new insights into toxic mechanisms associated with these diseases. Here, we review the influence of surfaces in driving and stabilizing protein aggregation with a specific emphasis on lipid membranes.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyloid disease; lipid membranes; prion disease; protein aggregation.

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Figures

Figure 1
Figure 1
A generic aggregation scheme for amyloid-forming proteins. Proteins fold into their native structure, which is typically a low free energy configuration. However, the energy landscape for protein folding often can have localized minima in which a protein can become trapped into a misfolded conformation, which can lead to aggregation into β-sheet rich amyloid fibrils. The formation of fibrils often proceeds through a heterogeneous mixture of intermediate species, including oligmers and protofibrils. Off-pathway aggregates can also form, such as annular aggregates. These aggregates accumulate into amyloid plaques or inclusions in the diseased brain. The aggregation pathway for any given amyloid-forming protein can vary considerably depending on the protein and its folding environment.
Figure 2
Figure 2
Aβ aggregation is modulated by the presence of chemically distinct solid surfaces. (A) On highly ordered pyrolytic graphite, Aβ aggregates into extended nanoribbons that are epitaxially ordered on the surface. The distinct orientation of Aβ aggregates on graphite is attributed to the optimization of the contact between the peptide and underlying hydrophobic carbon lattice. (B) On a negatively charged, hydrophilic mica surface, Aβ forms discrete oligomers that maintained some lateral mobility along the plane of the surface. These oligomers could organize into elongated protofibrillar structures. Schematic representations of the structure of each surface (graphite and mica) are provided under each image.
Figure 3
Figure 3
Point mutations in Aβ(1–40) modulate aggregate morphology in the presence of a mica surface. Using solution AFM, the aggregation of Wild Type, Arctic (E22G), and Italian (E22K) Aβ was monitored on a mica surface (Aβ concentration was 20 μM for all experiments). 5 μm × 5 μm images are presented in 3D with indicated zoomed in areas of 1 μm × 1 μm shown in 2D. (A) Wild Type Aβ formed a large population of oligomers (red arrows) and highly curved, elongated protofibrils (yellow arrows) with aggregate heights of ∼3–5 nm similar to presented in Figure 2. (B) Arctic Aβ formed rigid, branched, and highly ordered fibrillar aggregates (blue arrows) along the crystallographic lattice of mica with aggregate heights of ∼2–5 nm along the contour. These Arctic Aβ aggregates morphologically distinct from those formed by Wild Type Aβ. (C) Italian Aβ predominately aggregated into small oligomers (2–3 nm tall, red arrows) that coalesced into larger protofibrils (yellow arrows), in a similar fashion to Wild Type Aβ; however, a small number of rigid, elongated “Arctic-like” fibrillar aggregates of Italian Aβ also formed (blue arrow).
Figure 4
Figure 4
Schematic representations of potential mechanisms of amyloid/lipid association. (A) A schematic representation of simplified, undisrupted bilayer is presented. This bilayer structure can be perturbed by (B) amyloid-protein insertion or (C) association of amphiphilic α-helices lipid-binding domains. Such scenarios could lead to membrane thinning and non-specific membrane leakage. (D) Many amyloid-forming proteins have been shown to form pore-like structures that can act as unregulated ion-selective channels.
Figure 5
Figure 5
Point mutations in Aβ influence peptide aggregation in the presence of total brain lipid bilayers. Using solution AFM, aggregation of Wild Type, Arctic (E22G), or Italian (E22K) Aβ in the presence of supported TBLE bilayers was monitored (Aβ concentration was 20 μM for all experiments). 3D images are presented (4 μm × 4 μm and 6 μm × 6 μm) with indicated zoomed in areas of 1 μm × 1 μm and 2 μm × 2 μm shown in 2D. (A) With time, Wild Type Aβ aggregated into discrete oligomers and fibrils that were associated with regions of the bilayer with perturbed morphology (an increase in surface roughness). (B) While many small oligomers of Arctic Aβ were observed on the bilayer, highly curved fibrils that were associated with membrane disruption were the dominant aggregate species. These Arctic Aβ fibrils were morphologically distinct from fibrils observed for Wild Type Aβ. (C) While Italian Aβ also formed similar oligomers compared Wild Type and Arctic Aβ, large patches of disrupted bilayer morphology developed that may be associated with distinct fibril aggregates.
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