α-Casein Inhibits Insulin Amyloid Formation by Preventing the Onset of Secondary Nucleation Processes

Librizzi, Fabio; Carrotta, Rita; Spigolon, Dario; Bulone, Donatella; Biagio, Pier Luigi San

doi:10.1021/jz501570m

Cited by 25 publications

(27 citation statements)

References 61 publications

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“…7 Interestingly, although not directly related to this study, it has been shown in the literature that whey protein α or β caseins, usually present in the form of micelles through mutual hydrophobic and electrostatic interactions, show a chaperone-like activity in inhibiting amyloid beta and insulin from aggregation through mechanisms not yet understood. 37,38 Differently from cell membranes and SDS micelles that are net negative, zwitterionic LPCs readily disperse in water as ultrasmall micelles and subsequent interact with IAPP to halt the latter’s aggregation. Lastly, some LPC species are nearly 5 times more concentrated in the β-cell secretory granules compared to the rest of the cell, and are downregulated some 40–60% after glucose stimulation 39 suggesting a connection between LPC abundance and IAPP activity.…”

Section: Resultsmentioning

confidence: 99%

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Xing

Pilkington

Wang

et al. 2017

Phys. Chem. Chem. Phys.

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Amyloid aggregation of human islet amyloid polypeptide (IAPP) is a hallmark of type 2 diabetes (T2D), a metabolic disease and a global epidemic. Although IAPP is synthesized in pancreatic β-cells, its fibrils and plaques are found in the extracellular space indicating a causative transmembrane process. Numerous biophysical studies have revealed that cell membranes as well as model lipid vesicles promote the aggregation of amyloid-β (associated with Alzheimer’s), α-synuclein (associated with Parkinson’s) and IAPP, through electrostatic and hydrophobic interactions between the proteins/peptides and lipid membranes. Using a thioflavin T kinetic assay, transmission electron microscopy, circular dichroism spectroscopy, discrete molecular dynamics simulations as well as free energy calculations here we show that micellar lysophosphatidylcholine (LPC), the most abundant lysophospholipid in the blood, inhibited the amyloid aggregation of IAPP through nonspecific interactions while elevating the α-helical peptide secondary structure. This surprising finding suggests a native protective mechanism against IAPP aggregation in vivo.

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Section: Resultsmentioning

confidence: 99%

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Xing

Pilkington

Wang

et al. 2017

Phys. Chem. Chem. Phys.

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“…6,37,40,48,50 The nucleated aggregation of insulin typically results in an initial at lag phase, followed by a growth phase, and then a saturation phase. It is clear from Fig.…”

Section: The Aggregation Of Insulin At 333 Kmentioning

confidence: 99%

Differential influence of additives on the various stages of insulin aggregation

2016

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The kinetics of aggregation of insulin at pH 1.6 was studied by monitoring the turbidity as a function of time. The aggregation of insulin occurs by a typical nucleation-growth mechanism, resulting in a distinct lag phase, followed by a growth phase and a saturation phase. Sugars and polyols affect the lag time and the rate constant of growth to different extents, suggesting that these additives affect both the pre-and post-nucleation processes. Sucrose and ethylene glycol effectively reduce the aggregation, whereas mannitol is not effective in suppressing the overall aggregation. However, it can delay the aggregation process. It is also inferred that nucleation and elongation may not be affected in the same manner in the presence of a particular additive. The varying behaviour of different additives suggests their interference in the different stages of aggregation, affecting the aggregation intermediates differently. The viscosity of the medium has a minimal effect on the nucleation process, but does affect the elongation rate. The temperature dependence of the aggregation profiles provides probable reasons for the inhibitory action of these additives. The results also suggest the existence of different types of interactions between the additives and the various species in the aggregation pathway of insulin.

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“…It is still under argument that either an intermolecular hydrophobic force or electrostatic attraction is responsible for the amyloidogenesis. It is commonly accepted that fibrillogenesis is commenced due to the partial unfolding of insulin monomers, followed by their association to form protein oligomers and ß-sheet rich amyloid aggregates (Bekard and Dunstan, 2009 ; Librizzi et al, 2014 ). Consequently, understanding of the molecular basis of insulin fibrillation could be of great assessment in the direction of modeling the amyloidogenic pathways and toward developing delivery systems in the treatment of amyloid associated diseases.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity

et al. 2018

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Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches. Results showed that peptides employed different mechanisms to inhibit the amyloid fibrillation. Furthermore, they were also effective in blocking the amyloid fibrillation pathway. In contrary to the insulin fibrillar mesh, significantly less fibrillar species appeared in the presence of peptides, as confirmed by transmission electron microscopy. Circular dichroism analysis indicated that although peptides did not stabilize the native state of insulin, they inhibited amyloid aggregation by reducing the formation of β-sheet rich structures. Hemolytic assay revealed the non-hemolytic nature of the species formed when insulin was co-incubated with the peptides. Therefore, despite the inherent potential to form β-sheet structure, these peptides inhibited the amyloid formation and potentially can be used as therapeutics for the treatment of amyloid-related diseases.

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α-Casein Inhibits Insulin Amyloid Formation by Preventing the Onset of Secondary Nucleation Processes

Cited by 25 publications

References 61 publications

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Differential influence of additives on the various stages of insulin aggregation

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity

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