tailieunhanh - Báo cáo khoa học: The aggregation potential of human amylin determines its cytotoxicity towards islet b-cells

Human amylin is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type 2 dia-betes. There is evidence that it can elicitin vitro apoptosis in isletb-cells, but the physical properties that underpin its cytotoxicity have not been clearly elucidated. | iFEBS Journal The aggregation potential of human amylin determines its cytotoxicity towards islet 0-cells Barbara Konarkowska1 2 Jacqueline F. Aitken1 2 Joerg Kistler1 Shaoping Zhang1 2 and Garth J. S. Cooper1 2 3 1 Schoolof BiologicalSciences Faculty of Science University of Auckland New Zealand 2 Centre for Research Excellence in Molecular Biodiscovery Faculty of Science University of Auckland New Zealand 3 Department of Medicine Faculty of Medicaland Health Sciences University of Auckland New Zealand Keywords amylin amyloid formation pancreatic islet b-cells protein aggregation type 2 diabetes Correspondence G. J. S. Cooper Level4 Thomas Building Schoolof BiologicalSciences University of Auckland Private Bag 92019 Auckland New Zealand Fax 64 9 373 7045 Tel 64 9 373 7599 ext. 87394 E-mail Received 5 April2006 revised 6 June 2006 accepted 8 June 2006 doi Human amylin is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid which occurs in most subjects with type 2 diabetes. There is evidence that it can elicit in vitro apoptosis in islet b-cells but the physical properties that underpin its cytotoxicity have not been clearly elucidated. Here we employed electron microscopy thioflavin T fluorescence and CD spectroscopy to analyze amylin preparations whose cytotoxic potential was established by live-dead assay in cultured b-cells. Highly toxic amylin contained few preformed fibrils and initially showed little b-sheet content but underwent marked time-dependent aggregation and b-conformer formation following dissolution. By contrast low-toxicity amylin contained abundant preformed fibrils and demonstrated high initial b-sheet content but little propensity to aggregate further once dissolved. Thus mature amylin fibrils are not toxic to b-cells and aggregates of fibrils such as occur in pancreatic islet amyloid in vivo are unlikely to contribute to b-cell loss. Rather the toxic .

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