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

Burke KA, Yates EA, Legleiter J - Front Neurol (2013)

Bottom Line: 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.The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions.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.

View Article: PubMed Central - PubMed

Affiliation: C. Eugene Bennett Department of Chemistry, West Virginia University Morgantown, WV, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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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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.

Mentions: A potential mechanism for amyloid-forming proteins, such as Aβ, is their ability to alter membrane structure and integrity, leading to permeation of cellular membranes (Figure 4). Detergent-like effects arise from the amphiphilic nature of Aβ, leading to reduced membrane surface tension leading to membrane thinning and hole formation (Hebda and Miranker, 2009). Several AFM studies performed in solution have provided valuable insight into the aggregation of Aβ on a variety of model lipid membranes, leading to altered membrane morphology. The interaction of Aβ(1–40) with bilayers formed from total brain lipid extract (TBLE) revealed that Aβ(1–40) will partially insert into bilayers, growing into small fibers (Yip and McLaurin, 2001). In the same study, larger fiber-like structures associated with disruption of the bilayer morphology and integrity were observed as measured by increased surface roughness and formation of holes, respectively. Large fibrils were often highly branched and associated with edges of disrupted bilayer. The TBLE bilayers also aided in nucleation and enhancement of fibril growth. Interestingly, preformed fibrils were not capable of disrupting the TBLE bilayers, which may indicate that the act of aggregation, that is pre-fibrillar aggregates, may be key in Aβ-induced membrane disruption. Similar experiments exposing DMPC bilayers to Aβ(1–40) resulted in the formation of globular aggregates that were associated with small holes in the bilayer, whereas, fibril growth and/or extensive bilayer disruption was not observed. Aβ(1–42) demonstrated a different interaction/aggregation pattern on TBLE bilayers (Yip et al., 2002). Discrete molecules of Aβ(1–42) could be detected on the surface that were replaced by distinctly larger aggregates with time. However, bilayer defects were rarely detected upon exposure to Aβ(1–42). Point mutations in Aβ(1–40) also altered the aggregation on and ability to disrupt TBLE bilayers (Figure 5; Pifer et al., 2011). These same point mutations were shown to cause polymorphic aggregation of Aβ on mica. Aggregation in the presence of TBLE bilayers resulted in a variety of polymorphic aggregates in a mutation dependent manner and a variable ability to disrupt bilayer morphology/integrity. Such results highlight the potential role electrostatic and hydrophobic properties of Aβ play in its ability to bind, insert, and potentially disrupt lipid membranes.


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

Burke KA, Yates EA, Legleiter J - Front Neurol (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3585431&req=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.
Mentions: A potential mechanism for amyloid-forming proteins, such as Aβ, is their ability to alter membrane structure and integrity, leading to permeation of cellular membranes (Figure 4). Detergent-like effects arise from the amphiphilic nature of Aβ, leading to reduced membrane surface tension leading to membrane thinning and hole formation (Hebda and Miranker, 2009). Several AFM studies performed in solution have provided valuable insight into the aggregation of Aβ on a variety of model lipid membranes, leading to altered membrane morphology. The interaction of Aβ(1–40) with bilayers formed from total brain lipid extract (TBLE) revealed that Aβ(1–40) will partially insert into bilayers, growing into small fibers (Yip and McLaurin, 2001). In the same study, larger fiber-like structures associated with disruption of the bilayer morphology and integrity were observed as measured by increased surface roughness and formation of holes, respectively. Large fibrils were often highly branched and associated with edges of disrupted bilayer. The TBLE bilayers also aided in nucleation and enhancement of fibril growth. Interestingly, preformed fibrils were not capable of disrupting the TBLE bilayers, which may indicate that the act of aggregation, that is pre-fibrillar aggregates, may be key in Aβ-induced membrane disruption. Similar experiments exposing DMPC bilayers to Aβ(1–40) resulted in the formation of globular aggregates that were associated with small holes in the bilayer, whereas, fibril growth and/or extensive bilayer disruption was not observed. Aβ(1–42) demonstrated a different interaction/aggregation pattern on TBLE bilayers (Yip et al., 2002). Discrete molecules of Aβ(1–42) could be detected on the surface that were replaced by distinctly larger aggregates with time. However, bilayer defects were rarely detected upon exposure to Aβ(1–42). Point mutations in Aβ(1–40) also altered the aggregation on and ability to disrupt TBLE bilayers (Figure 5; Pifer et al., 2011). These same point mutations were shown to cause polymorphic aggregation of Aβ on mica. Aggregation in the presence of TBLE bilayers resulted in a variety of polymorphic aggregates in a mutation dependent manner and a variable ability to disrupt bilayer morphology/integrity. Such results highlight the potential role electrostatic and hydrophobic properties of Aβ play in its ability to bind, insert, and potentially disrupt lipid membranes.

Bottom Line: 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.The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions.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.

View Article: PubMed Central - PubMed

Affiliation: C. Eugene Bennett Department of Chemistry, West Virginia University Morgantown, WV, USA.

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.

No MeSH data available.


Related in: MedlinePlus