Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane
- 22 April 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (16), 6033-6038
- https://doi.org/10.1073/pnas.0708354105
Abstract
Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulin-producing islet beta cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this beta cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.Keywords
This publication has 49 references indexed in Scilit:
- Mechanism of Islet Amyloid Polypeptide Fibrillation at Lipid Interfaces Studied by Infrared Reflection Absorption SpectroscopyBiophysical Journal, 2007
- Membrane fragmentation by an amyloidogenic fragment of human Islet Amyloid Polypeptide detected by solid-state NMR spectroscopy of membrane nanotubesBiochimica et Biophysica Acta (BBA) - Biomembranes, 2007
- Formation of Toxic Fibrils of Alzheimer’s Amyloid β-Protein-(1–40) by Monosialoganglioside GM1, a Neuronal Membrane ComponentJournal of Molecular Biology, 2007
- Fiber-dependent amyloid formation as catalysis of an existing reaction pathwayProceedings of the National Academy of Sciences of the United States of America, 2007
- Lysozyme Amyloid Oligomers and Fibrils Induce Cellular Death via Different Apoptotic/Necrotic PathwaysJournal of Molecular Biology, 2007
- Islet Amyloid Polypeptide Inserts into Phospholipid Monolayers as MonomerJournal of Molecular Biology, 2006
- Islet amyloid polypeptide‐induced membrane leakage involves uptake of lipids by forming amyloid fibersFEBS Letters, 2004
- Phospholipid Catalysis of Diabetic Amyloid AssemblyJournal of Molecular Biology, 2004
- Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of PathogenesisScience, 2003
- Effects of beta cell granule components on human islet amyloid polypeptide fibril formationFEBS Letters, 1996