Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

Birol, Melissa; Kumar, Sunil; Rhoades, Elizabeth; Miranker, Andrew D.

doi:10.1038/s41467-018-03651-9

Cited by 57 publications

(57 citation statements)

References 33 publications

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“…ER stress induces changes towards a more reducing cellular environment, which triggers amylin aggregation [ 111 ]. A very recent publication brings new insight into IAPP conformational structure requirements for the formation of pores and the cytotoxic mechanisms in diabetes [ 112 ]. IAPP-induced toxicity eventually triggers autophagy as a response to protect against ER-related cellular damage [ 113 , 114 ].…”

Section: Er Stress Induces Ir and Diabetesmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Metabolic Disorders

Ghemrawi

Battaglia-Hsu

Arnold

2018

Cells

155

113

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Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these diseases has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic disturbance stemmed from over nutrition frequently aggravated by a modern, sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults (Mukherjee, et al., 2015). In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

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Section: Er Stress Induces Ir and Diabetesmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Metabolic Disorders

Ghemrawi

Battaglia-Hsu

Arnold

2018

Cells

155

113

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“…Human amylin induces cell membrane permeabilization and perturbation, endoplasmic reticulum (ER) stress, mitochondrial damage, and β-cell death [ 84 , 85 , 86 , 87 , 88 ]. Furthermore, human amylin extracellularly added to INS-1β-cells at toxic concentrations crosses the plasma membrane and approximately 50% of amylin is localized in mitochondria and 5% or less is localized in the ER [ 89 ]. Human amylin forms oligomers that subsequently form fibrils followed by amyloid deposits [ 90 ].…”

Section: Cytotoxicity Of Amylinmentioning

confidence: 99%

“…Orcein-related small molecule, O4, is another chemical chaperone that induces the disaggregation of human amylin [ 119 ]. ADM-116, a pentaquinoline foldamer, can permeate the plasma membrane and prevent mitochondrial damage induced by amylin [ 89 ]. Furthermore, ADM-116 prevents the formation of amylin aggregates, thereby protecting pancreatic islet β-cells from the cytotoxic effects of amylin [ 120 ].…”

Section: Protection Of Pancreatic Islet β-Cells From Cytotoxicity mentioning

confidence: 99%

Role and Cytotoxicity of Amylin and Protection of Pancreatic Islet β-Cells from Amylin Cytotoxicity

Kiriyama

Nochi

2018

Cells

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Amylin, (or islet amyloid polypeptide; IAPP), a 37-amino acid peptide hormone, is released in response to nutrients, including glucose, lipids or amino acids. Amylin is co-stored and co-secreted with insulin by pancreatic islet β-cells. Amylin inhibits food intake, delays gastric emptying, and decreases blood glucose levels, leading to the reduction of body weight. Therefore, amylin as well as insulin play important roles in controlling the level of blood glucose. However, human amylin aggregates and human amylin oligomers cause membrane disruption, endoplasmic reticulum (ER) stress and mitochondrial damage. Since cytotoxicity of human amylin oligomers to pancreatic islet β-cells can lead to diabetes, the protection of pancreatic islet β cells from cytotoxic amylin is crucial. Human amylin oligomers also inhibit autophagy, although autophagy can function to remove amylin aggregates and damaged organelles. Small molecules, including β-sheet breaker peptides, chemical chaperones, and foldamers, inhibit and disaggregate amyloid formed by human amylin, suggesting the possible use of these small molecules in the treatment of diabetes. In this review, we summarize recent findings regarding the role and cytotoxicity of amylin and the protection of pancreatic islet β-cells from cytotoxicity of amylin.

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“…[3] Previous studies also reported that hIAPP forms toxic oligomers, which are alpha-helical. [4][5][6] Because of the cellular toxicity that associates with amyloid formation, it is important to develop small molecule compounds that inhibit/prevent amyloid aggregation and toxicity. [7] One of the frequently investigated amyloid inhibitors is epigallocatechin-gallate (EGCG; the major catechin present in green tea) ( Fig.S1B), a polyphenolic compound found in green tea extract.…”

Section: Introductionmentioning

confidence: 99%

Zinc Boosts EGCG’s hIAPP Amyloid Inhibition Both in Solution and Membrane

Lee

Lin

Cox

et al. 2018

Preprint

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Amyloid aggregation of human islet amyloid polypeptide (hIAPP) is linked to insulin-producing islet cell death in type II diabetes. Previous studies have shown the amyloid inhibiting effects of zinc (Zn) and insulin that are co-present with hIAPP in islet cells, and the lipid membrane has been shown to significantly influence the aggregation kinetics. Increasing number of studies report the importance of developing small molecule inhibitors to suppress the hIAPP's toxicity.Particularly, the ability of epigallocatechin-gallate (EGCG) to inhibit amyloid aggregation of a variety of amyloid peptide/proteins including hIAPP initiated numerous studies including the development of compounds to potentially treat amyloid diseases. In this study, by using a combination of thioflavin-T fluorescence and transmission electron microscopy experiments, we demonstrate a significant enhancement in EGCG's efficiency, when mixed with Zn, to significantly suppress hIAPP amyloid aggregation both in presence and absence of lipid membrane. Circular dichroism experiments indicate the formation and stabilization of a helical structure of hIAPP in presence of EGCG:Zn complex. Our results also reveal the ability of EGCG or EGCG:Zn to suppress hIAPP's cellular toxicity and that the ability of EGCG to chelate with Zn suppresses zinc's cellular toxicity. We suggest that the reported results would be useful to develop strategies to trap hIAPP intermediates for further biophysical and structural studies, and also to devise approaches to abolish amyloid aggregation and cellular toxicity.

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Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

Cited by 57 publications

References 33 publications

Endoplasmic Reticulum Stress in Metabolic Disorders

Endoplasmic Reticulum Stress in Metabolic Disorders

Role and Cytotoxicity of Amylin and Protection of Pancreatic Islet β-Cells from Amylin Cytotoxicity

Zinc Boosts EGCG’s hIAPP Amyloid Inhibition Both in Solution and Membrane

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