scholarly journals The kinetics of islet amyloid polypeptide phase separated system and hydrogel formation are critically influenced by macromolecular crowding

2021 ◽  
Author(s):  
Lior Pytowski ◽  
David Vaux ◽  
Létitia Jean
Keyword(s):  
Type Ii Diabetes ◽  
Volume Fraction ◽  
Biological Fluids ◽  
Islet Amyloid Polypeptide ◽  
Macromolecular Crowding ◽  
Type Ii ◽  
Amyloid Aggregation ◽  
Islet Amyloid ◽  
Kinetics Of

Many protein misfolding diseases (e.g. type II diabetes and Alzheimer’s disease) are characterised by amyloid deposition. Human islet amyloid polypeptide (hIAPP, involved in type II diabetes) spontaneously undergoes liquid-liquid phase separation (LLPS) and a kinetically complex hydrogelation, both catalysed by hydrophobic-hydrophilic interfaces (e.g. air-water interface and/or phospholipids-water interfaces). Gelation of hIAPP phase separated liquid droplets initiates amyloid aggregation and formation of clusters of interconnected aggregates, which grow and fuse to eventually percolate the whole system. Droplet maturation into irreversible hydrogels via amyloid aggregation is thought to be behind the pathology of several diseases. Biological fluids contain a high volume fraction of macromolecules, leading to macromolecular crowding. Despite crowding agent addition in in vitro studies playing a significant role in changing protein phase diagrams, the mechanism underlying enhanced LLPS, and the effect(s) on stages beyond LLPS remain poorly or not characterised.  We investigated the effect of macromolecular crowding and increased viscosity on the kinetics of hIAPP hydrogelation using rheology and the evolution of the system beyond LLPS by microscopy. We demonstrate that increased viscosity exacerbated the kinetic variability of hydrogelation and of the phase separated-aggregated system, whereas macromolecular crowding abolished heterogeneity. Increased viscosity also strengthened the gel meshwork and accelerated aggregate cluster fusion. In contrast, crowding either delayed cluster fusion onset (dextran) or promoted it (Ficoll). Our study highlights that an in vivo crowded environment would critically influence amyloid stages beyond LLPS and pathogenesis.

scholarly journals γ-AApeptides–based Small Molecule Ligands That Disaggregate Human Islet Amyloid Polypeptide

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Olapeju Bolarinwa ◽  
Chunpu Li ◽  
Nawal Khadka ◽  
Qi Li ◽  
Yan Wang ◽  
...  
Keyword(s):  
Type Ii Diabetes ◽  
Islet Amyloid Polypeptide ◽  
Typical Feature ◽  
Human Islet ◽  
Type Ii ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Age Related ◽  
Small Molecule Ligands ◽  
Human Amylin

AbstractThe abnormal folding and aggregation of functional proteins into amyloid is a typical feature of many age-related diseases, including Type II diabetes. Growing evidence has revealed that the prevention of aggregate formation in culprit proteins could retard the progression of amyloid diseases. Human Amylin, also known as human islet amyloid polypeptide (hIAPP), is the major factor for categorizing Type II diabetes as an amyloid disease. Specifically, hIAPP has a great aggregation potential, which always results in a lethal situation for the pancreas. Many peptide inhibitors have been constructed from the various segments of the full-length hIAPP peptide; however, only a few have their origin from the screening of combinatorial peptidomimetic library. In this study, based on HW-155, which was previously discovered from a one–bead–one compound (OBOC) library to inhibit Aβ40 aggregation, we investigated eight (8) analogues and evaluated their amyloid-prevention capabilities for inhibiting fibrillization of hIAPP. Characterization studies revealed that all analogues of HW-155, as well as HW-155, were effective inhibitors of the fibril formation by hIAPP.

scholarly journals Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Phuong Trang Nguyen ◽  
Nagore Andraka ◽  
Carole Anne De Carufel ◽  
Steve Bourgault
Keyword(s):  
Type Ii Diabetes ◽  
Amyloid Fibrils ◽  
Driving Forces ◽  
Islet Amyloid Polypeptide ◽  
Type Ii Diabetes Mellitus ◽  
Major Protein ◽  
Local Concentration ◽  
Amyloid Formation ◽  
Type Ii ◽  
Islet Amyloid

Type II diabetes mellitus is associated with the deposition of fibrillar aggregates in pancreatic islets. The major protein component of islet amyloids is the glucomodulatory hormone islet amyloid polypeptide (IAPP). Islet amyloid fibrils are virtually always associated with several biomolecules, including apolipoprotein E, metals, glycosaminoglycans, and various lipids. IAPP amyloidogenesis has been originally perceived as a self-assembly homogeneous process in which the inherent aggregation propensity of the peptide and its local concentration constitute the major driving forces to fibrillization. However, over the last two decades, numerous studies have shown a prominent role of amyloid cofactors in IAPP fibrillogenesis associated with the etiology of type II diabetes. It is increasingly evident that the biochemical microenvironment in which IAPP amyloid formation occurs and the interactions of the polypeptide with various biomolecules not only modulate the rate and extent of aggregation, but could also remodel the amyloidogenesis process as well as the structure, toxicity, and stability of the resulting fibrils.

scholarly journals Multiphasic effect of vinyl pyrrolidone polymers on amyloidogenesis, from macromolecular crowding to inhibition

2018 ◽  
Vol 475 (21) ◽  
pp. 3417-3436 ◽  
Author(s):  
Richard Berwick ◽  
David J. Vaux ◽  
Létitia Jean
Keyword(s):  
Molecular Mass ◽  
Surface Activity ◽  
Type Ii Diabetes ◽  
Volume Fraction ◽  
Macromolecular Crowding ◽  
Monomer Concentration ◽  
Vinyl Pyrrolidone ◽  
Bulk Solution ◽  
Type Ii

Deposition of misfolded amyloid polypeptides, associated with cell death, is the hallmark of many degenerative diseases (e.g. type II diabetes mellitus and Alzheimer's disease). In vivo, cellular and extracellular spaces are occupied by a high volume fraction of macromolecules. The resulting macromolecular crowding energetically affects reactions. Amyloidogenesis can either be promoted by macromolecular crowding through the excluded volume effect or inhibited due to a viscosity increase reducing kinetics. Macromolecular crowding can be mimicked in vitro by the addition of non-specific polymers, e.g. Ficoll, dextran and polyvinyl pyrrolidone (PVP), the latter being rarely used to study amyloid systems. We investigated the effect of PVP on amyloidogenesis of full-length human islet amyloid polypeptide (involved in type II diabetes) using fibrillisation and surface activity assays, ELISA, immunoblot and microscale thermophoresis. We demonstrate that high molecular mass PVP360 promotes amyloidogenesis due to volume exclusion and increase in effective amyloidogenic monomer concentration, like other crowders, but without the confounding effects of viscosity and surface activity. Interestingly, we also show that low molecular mass PVP10 has unique inhibitory properties as inhibition of fibril elongation occurs mainly in the bulk solution and is due to PVP10 directly and strongly interacting with amyloid species rather than the increase in viscosity typically associated with macromolecular crowding. In vivo, amyloidogenesis might be affected by the properties and proximity of endogenous macromolecular crowders, which could contribute to changes in associated pathogenesis. More generally, the PVP10 molecular backbone could be used to design small compounds as potential inhibitors of toxic species formation.

Amyloid protein in somatostatinoma differs from human islet amyloid polypeptide

1991 ◽  
Vol 124 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Haruhiko Ohsawa ◽  
Azuma Kanatsuka ◽  
Yoshiharu Tokuyama ◽  
Takahide Yamaguchi ◽  
Hideichi Makino ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type Ii Diabetes ◽  
Islet Amyloid Polypeptide ◽  
Type Ii Diabetes Mellitus ◽  
Pancreatic Tissue ◽  
Type Ii ◽  
Pancreatic Hormones ◽  
Islet Amyloid ◽  
Electron Microscopic ◽  
Amyloid Deposits

Abstract. Amyloid deposits in somatostatinomas are rare observations. To examine the characteristics of this amyloid, we compared amyloid deposits in a somatostatinoma to those found in pancreatic tissue in patients with Type II diabetes mellitus and in insulinomas, using immunohistochemical techniques and specific antibodies to islet amyloid polypeptide or other pancreatic hormones, as well as electron-microscopy. Antibodies to islet amyloid polypeptide regions 8-17 or 25-37 were confirmed to be specific. Amyloid deposits in patients with Type II diabetes mellitus and in insulinomas, but not those in the somatostatinoma strongly reacted with these antibodies, or to an antibody to amyloid P component. Amyloid deposits in the somatostatinoma were not reactive with antibodies to somatostatin or to other pancreatic hormones. Electron-microscopic examinations revealed that amyloid fibrils in the somatostatinoma were thinner and more randomly distributed than were those in islets from patients with Type II diabetes mellitus. As amyloid in somatostatinomas is unlike that consisting of islet amyloid polypeptide or other mature pancreatic hormones, it may be a novel type of local amyloid in pancreatic islets.

scholarly journals Influence of Aluminium and EGCG on Fibrillation and Aggregation of Human Islet Amyloid Polypeptide

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Zhi-Xue Xu ◽  
Qiang Zhang ◽  
Gong-Li Ma ◽  
Cong-Heng Chen ◽  
Yan-Ming He ◽  
...  
Keyword(s):  
Type Ii Diabetes ◽  
Islet Amyloid Polypeptide ◽  
Epigallocatechin Gallate ◽  
Inhibitory Effect ◽  
Human Islet ◽  
Molar Ratio ◽  
Type Ii ◽  
Amyloid Proteins ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (−)-epigallocatechin gallate (EGCG) is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III)/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III) and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III) and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III) could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III)/EGCG complex in molar ratio of 1 : 1 as Al(EGCG)(H2O)2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes.

scholarly journals How Type II Diabetes-Related Islet Amyloid Polypeptide Damages Lipid Bilayers

2012 ◽  
Vol 102 (5) ◽  
pp. 1059-1068 ◽  
Author(s):  
Chang-Chun Lee ◽  
Yen Sun ◽  
Huey W. Huang
Keyword(s):  
Lipid Bilayers ◽  
Type Ii Diabetes ◽  
Islet Amyloid Polypeptide ◽  
Type Ii ◽  
Islet Amyloid
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