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Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.

Abedini A, Plesner A, Cao P, Ridgway Z, Zhang J, Tu LH, Middleton CT, Chao B, Sartori DJ, Meng F, Wang H, Wong AG, Zanni MT, Verchere CB, Raleigh DP, Schmidt AM - Elife (2016)

Bottom Line: These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species.They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure.Aromatic interactions modulate, but are not required for toxicity.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.

ABSTRACT
Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 β-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced β-cell death.

No MeSH data available.


Related in: MedlinePlus

A schematic diagram of the process of amyloid formation by h-IAPP.(A) Amino acid sequence of wild-type h-IAPP. The mature, bioactive form of the polypeptide has an amidated C-terminus and a disulfide bridge indicated by the bracket between Cys-2 and Cys-7. (B) Schematic diagram illustrating the kinetics of amyloid formation by h-IAPP. The ribbon diagram shown is derived from the IAPP model developed by Eisenberg and co-workers (Wiltzius et al., 2009).DOI:http://dx.doi.org/10.7554/eLife.12977.002
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fig1: A schematic diagram of the process of amyloid formation by h-IAPP.(A) Amino acid sequence of wild-type h-IAPP. The mature, bioactive form of the polypeptide has an amidated C-terminus and a disulfide bridge indicated by the bracket between Cys-2 and Cys-7. (B) Schematic diagram illustrating the kinetics of amyloid formation by h-IAPP. The ribbon diagram shown is derived from the IAPP model developed by Eisenberg and co-workers (Wiltzius et al., 2009).DOI:http://dx.doi.org/10.7554/eLife.12977.002

Mentions: The pathophysiological aggregation of polypeptides and proteins plays a key role in a wide range of protein misfolding diseases, including type 2 diabetes (T2D), Alzheimer’s disease (AD) and systemic amyloidosis. Pancreatic islet amyloidosis by the neuropancreatic hormone, human islet amyloid polypeptide (h-IAPP, also known as amylin) contributes to β-cell death, progression of T2D, islet transplant failure, as well as cardiovascular complications (Figure 1) (Potter et al., 2010; Ashcroft and Rorsman, 2012; Westermark et al., 2008; Despa et al., 2012; Abedini and Schmidt, 2013; Cao et al., 2013a). Relatively little is known about the molecular properties that define the toxic species produced during amyloid formation (Abedini and Schmidt, 2013; Cao et al., 2013a; Westermark et al., 1987; Cooper et al., 1987; Campioni et al., 2010; Chiti and Dobson, 2006; Johnson et al., 2012; Eisenberg and Jucker, 2012; Blancas-Mejía and Ramirez-Alvarado, 2013), particularly in islet amyloidosis.10.7554/eLife.12977.002Figure 1.A schematic diagram of the process of amyloid formation by h-IAPP.


Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.

Abedini A, Plesner A, Cao P, Ridgway Z, Zhang J, Tu LH, Middleton CT, Chao B, Sartori DJ, Meng F, Wang H, Wong AG, Zanni MT, Verchere CB, Raleigh DP, Schmidt AM - Elife (2016)

A schematic diagram of the process of amyloid formation by h-IAPP.(A) Amino acid sequence of wild-type h-IAPP. The mature, bioactive form of the polypeptide has an amidated C-terminus and a disulfide bridge indicated by the bracket between Cys-2 and Cys-7. (B) Schematic diagram illustrating the kinetics of amyloid formation by h-IAPP. The ribbon diagram shown is derived from the IAPP model developed by Eisenberg and co-workers (Wiltzius et al., 2009).DOI:http://dx.doi.org/10.7554/eLife.12977.002
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940161&req=5

fig1: A schematic diagram of the process of amyloid formation by h-IAPP.(A) Amino acid sequence of wild-type h-IAPP. The mature, bioactive form of the polypeptide has an amidated C-terminus and a disulfide bridge indicated by the bracket between Cys-2 and Cys-7. (B) Schematic diagram illustrating the kinetics of amyloid formation by h-IAPP. The ribbon diagram shown is derived from the IAPP model developed by Eisenberg and co-workers (Wiltzius et al., 2009).DOI:http://dx.doi.org/10.7554/eLife.12977.002
Mentions: The pathophysiological aggregation of polypeptides and proteins plays a key role in a wide range of protein misfolding diseases, including type 2 diabetes (T2D), Alzheimer’s disease (AD) and systemic amyloidosis. Pancreatic islet amyloidosis by the neuropancreatic hormone, human islet amyloid polypeptide (h-IAPP, also known as amylin) contributes to β-cell death, progression of T2D, islet transplant failure, as well as cardiovascular complications (Figure 1) (Potter et al., 2010; Ashcroft and Rorsman, 2012; Westermark et al., 2008; Despa et al., 2012; Abedini and Schmidt, 2013; Cao et al., 2013a). Relatively little is known about the molecular properties that define the toxic species produced during amyloid formation (Abedini and Schmidt, 2013; Cao et al., 2013a; Westermark et al., 1987; Cooper et al., 1987; Campioni et al., 2010; Chiti and Dobson, 2006; Johnson et al., 2012; Eisenberg and Jucker, 2012; Blancas-Mejía and Ramirez-Alvarado, 2013), particularly in islet amyloidosis.10.7554/eLife.12977.002Figure 1.A schematic diagram of the process of amyloid formation by h-IAPP.

Bottom Line: These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species.They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure.Aromatic interactions modulate, but are not required for toxicity.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States.

ABSTRACT
Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 β-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced β-cell death.

No MeSH data available.


Related in: MedlinePlus