Lipids uniquely alter secondary structure and toxicity of lysozyme aggregates

Matveyenka, Mikhail; Zhaliazka, Kiryl; Rizevsky, Stanislav; Kurouski, Dmitry

doi:10.1096/fj.202200841r

Cited by 24 publications

(81 citation statements)

References 54 publications

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“…34 In this case, endosomal damage is followed by enhanced ROS levels and mitochondrial damage that ultimately led to cell death. 34,54 Matveyenka and co-workers also found that amyloid aggregates caused significant damage of cell endoplasmic reticulum via the activation of unfolded protein response. 62 These results demonstrate that amyloid-induced cell death can involve multiple molecular mechanisms.…”

Section: ■ Discussionmentioning

confidence: 98%

“…Lipids are a large class of biological molecules that perform a large number of physiologically important functions in cells. − Lipids are the major components of plasma and organelle membranes that determine membrane fluidity and permeability for molecules and ions. Lipids also act as secondary messengers in signal transduction across the plasma membrane . It was recently reported that amyloid proteins can interact with lipids forming complexes that have enhanced hydrophobicity .…”

Section: Discussionmentioning

confidence: 99%

“…Lipids also act as secondary messengers in signal transduction across the plasma membrane. 54 It was recently reported that amyloid proteins can interact with lipids forming complexes that have enhanced hydrophobicity. 17 This allows for such amyloid:lipid structures to pass thorough the lipid bilayers into the cytosol, where they trigger ROS production and endoplasmic reticulum stress, ultimately causing cell death.…”

Section: Discussionmentioning

confidence: 99%

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Elucidation of the Effect of Phospholipid Charge on the Rate of Insulin Aggregation and Structure and Toxicity of Amyloid Fibrils

2023

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The plasma membrane is a dynamic structure that separates the cell interior from the extracellular space. The fluidity and plasticity of the membrane determines a large number of physiologically important processes ranging from cell division to signal transduction. In turn, membrane fluidity is determined by phospholipids that possess different charges, lengths, and saturation states of fatty acids. A growing body of evidence suggests that phospholipids may play an important role in the aggregation of misfolded proteins, which causes pathological conditions that lead to severe neurodegenerative diseases. In this study, we investigate the role of the charge of the most abundant phospholipids in the plasma membrane: phosphatidylcholine and phosphatidylethanolamine, zwitterions: phosphatidylserine and phosphatidylglycerol, lipids that possess a negative charge, and cardiolipin that has double negative charge on its polar head. Our results show that both zwitterions strongly inhibit insulin aggregation, whereas negatively charged lipids accelerate fibril formation. We also found that in the equimolar presence of zwitterions insulin yields oligomers that exert significantly lower cell toxicity compared to fibrils that were grown in the lipid-free environment. Such aggregates were not formed in the presence of negatively charged lipids. Instead, long insulin fibrils that had strong cell toxicity were grown in the presence of such negatively charged lipids. However, our results showed no correlation between the charge of the lipid and secondary structure and toxicity of the aggregates formed in its presence. These findings show that the secondary structure and toxicity are determined by the chemical structure of the lipid rather than by the charge of the phospholipid polar head.

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Section: ■ Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Elucidation of the Effect of Phospholipid Charge on the Rate of Insulin Aggregation and Structure and Toxicity of Amyloid Fibrils

2023

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“…These results are in a good agreement with the findings of Matveyenka et al . [61,76–80] which demonstrated that toxicity of insulin and lysozyme aggregates could be uniquely altered by lipids. Specifically, it was found that presence of PC at 1 : 1 molar ratios with insulin and lysozyme resulted in formation of small oligomers that exerted nearly three times lower cell toxicity compared to proteins fibrils grown in the lipid‐free environment [76–78].…”

Section: Discussionmentioning

confidence: 99%

Lipids uniquely alter the secondary structure and toxicity of amyloid beta 1–42 aggregates

2023

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Abrupt aggregation of amyloid β1‐42 (Aβ) peptide is a hallmark of Alzheimer's disease (AD), a severe pathology that affects more than 44 million people worldwide. A growing body of evidence suggests that lipids can uniquely alter rates of Aβ1‐42 aggregation. However, it remains unclear whether lipids only alter rates of protein aggregation or also uniquely modify the secondary structure and toxicity of Aβ1‐42 oligomers and fibrils. In this study, we investigated the effect of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Chol) on Aβ1‐42 aggregation. We found that PC, CL and Chol strongly accelerated the rate of fibril formation compared to the rate of Aβ1‐42 aggregation in the lipid‐free environment. Furthermore, anionic CL enabled the strongest acceleration of Aβ1‐42 aggregation compared to zwitterionic PC and uncharged Chol. We also found that PC, CL and Chol uniquely altered the secondary structure of early‐, middle‐ and late‐stage Aβ1‐42 aggregates. Specifically, CL and Chol drastically increased the amount of parallel β‐sheet in Aβ1‐42 oligomers and fibrils grown in the presence of these lipids. This caused a significant increase in the toxicity of Aβ : CL and Aβ : Chol compared to the toxicity of Aβ : PC and Aβ1‐42 aggregates formed in the lipid‐free environment. These results demonstrate that toxicity of Aβ aggregates correlates with the amount of their β‐sheet content, which, in turn, is determined by the chemical structure of lipids present at the stage of Aβ1‐42 aggregation.

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“…Specifically, the equimolar presence of fully saturated PS enabled the strongest enhancement of the rate of insulin aggregation compared to PS with unsaturated fatty acids. It was also found that insulin and lysozyme aggregates formed in the presence of PS exerted significantly different cell toxicities compared to the fibrils grown in the lipid-free environment. ,, Although the above-discussed findings can be valuable for the understanding of the role of PS in amyloidosis, they were obtained upon exposition of both insulin and lysozyme to the large unilamellar vesicles (LUVs) composed of PS alone. ,, The question to ask is whether an increase in the concentration of PS relative to zwitterionic lipids, such as PC and phosphatidylethanolamine (PE), primary constituents of the plasma membranes of most eucaryotic cells, would alter the rate of protein aggregation, as was evident for PS itself. To answer this question, we used a set of biophysical and molecular biology techniques that allowed for the determination of the rate of protein aggregation, the elucidation of morphology, secondary structure, and the toxicity of protein aggregates grown in the presence of lipid mixtures and in the lipid-free environment.…”

Section: Introductionmentioning

confidence: 99%

Concentration of Phosphatidylserine Influence Rates of Insulin Aggregation and Toxicity of Amyloid Aggregates In Vitro

Matveyenka

Zhaliazka

Kurouski

2023

ACS Chem. Neurosci.

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Phosphatidylserine (PS) is a negatively charged lipid that plays a critically important role in cell apoptosis. Under physiological conditions, PS is localized on the cytosolic side of plasma membranes via ATP-dependent flippase-mediated transport. A decrease in the ATP levels in the cell, which is taken place upon pathological processes, results in the increase in PS concentration on the exterior part of the cell membranes. PS on the outer membrane surfaces attracts and activates phagocytes, which trigger cell apoptosis. This programed irreversible cell death is observed upon the progressive neurodegeneration, a hallmark of numerous amyloid associated pathologies, such as diabetes type 2 and Alzheimer’s disease. In this study, we investigate the extent to which the rates of protein aggregation, which occurs upon amyloid pathologies, can be altered by the concentration of PS in large unilamellar vesicles (LUVs). We found that with an increase in the concentration of PS from 20 to 40% relative to the concentration of phosphatidylcholine and phosphatidylethanolamine, the rate of insulin aggregation, protein linked to diabetes type 2, and injection amyloidosis drastically increased. Furthermore, the concentration of PS in LUVs determined the secondary structure of protein aggregates formed in their presence. We also found that these structurally different aggregates exerted distinctly different cell toxicities. These findings suggest that a substantial decrease in cell viability, which is likely to take place upon aging, results in the increase in the concentration of PS in the outer plasma membranes, where it triggers the irreversible self-assembly of amyloidogenic proteins, which, in turn, causes the progressive neurodegeneration.

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Lipids uniquely alter secondary structure and toxicity of lysozyme aggregates

Abstract: time when the intensity of ThT fluorescence reached 50% of the maximum; tgrow, time when the intensity of ThT fluorescence reached 90% of the maximum; ThT, thioflavin T; tlag, time when the intensity of ThT fluorescence reached 10% of the maximum.

Cited by 24 publications

References 54 publications

Elucidation of the Effect of Phospholipid Charge on the Rate of Insulin Aggregation and Structure and Toxicity of Amyloid Fibrils

Elucidation of the Effect of Phospholipid Charge on the Rate of Insulin Aggregation and Structure and Toxicity of Amyloid Fibrils

Lipids uniquely alter the secondary structure and toxicity of amyloid beta 1–42 aggregates

Concentration of Phosphatidylserine Influence Rates of Insulin Aggregation and Toxicity of Amyloid Aggregates In Vitro

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