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Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates
Diseases such as type 2 diabetes, Alzheimer’s and Parkinson’s share as common feature the accumulation of mis-folded disease-specific protein aggregates into fibrillar structures, or plaques. These fibrils may either be toxic by themselves, or act as reservoirs for smaller cytotoxic oligomers. This...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014569/ https://www.ncbi.nlm.nih.gov/pubmed/24810618 http://dx.doi.org/10.1371/journal.pone.0097051 |
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author | Berhanu, Workalemahu M. Hansmann, Ulrich H. E. |
author_facet | Berhanu, Workalemahu M. Hansmann, Ulrich H. E. |
author_sort | Berhanu, Workalemahu M. |
collection | PubMed |
description | Diseases such as type 2 diabetes, Alzheimer’s and Parkinson’s share as common feature the accumulation of mis-folded disease-specific protein aggregates into fibrillar structures, or plaques. These fibrils may either be toxic by themselves, or act as reservoirs for smaller cytotoxic oligomers. This suggests to investigate molecules as potential therapeutics that either reduce fibril formation or increase fibril stability. One example is rat amylin, which can inhibit aggregation of human amylin, a hallmark of type 2 diabetes. In the present paper, we use molecular dynamics to compare the stability of various preformed aggregates, built out of either human amylin, rat amylin, or mixtures of both. We considered two types of fibril-like oligomers: a single-layer in-register conformation, and a double-layer conformation in which the first U-shaped layer consists of rat amylin and the second layer of human amylin. Our results explain the weak amyloid-inhibiting properties of rat amylin and suggest that membrane leakage due to pore formation is responsible for the toxicity of rat amylin observed in a recent experiment. Together, our results put in question the use of rat amylin or the similar FDA approved drug pramlintide as an inhibitor of human amylin aggregation. They also point to mixed human-rat amylin fibril-like oligomers as possible model-systems for studies of amyloid formation that involve cross-species transmission. |
format | Online Article Text |
id | pubmed-4014569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40145692014-05-14 Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates Berhanu, Workalemahu M. Hansmann, Ulrich H. E. PLoS One Research Article Diseases such as type 2 diabetes, Alzheimer’s and Parkinson’s share as common feature the accumulation of mis-folded disease-specific protein aggregates into fibrillar structures, or plaques. These fibrils may either be toxic by themselves, or act as reservoirs for smaller cytotoxic oligomers. This suggests to investigate molecules as potential therapeutics that either reduce fibril formation or increase fibril stability. One example is rat amylin, which can inhibit aggregation of human amylin, a hallmark of type 2 diabetes. In the present paper, we use molecular dynamics to compare the stability of various preformed aggregates, built out of either human amylin, rat amylin, or mixtures of both. We considered two types of fibril-like oligomers: a single-layer in-register conformation, and a double-layer conformation in which the first U-shaped layer consists of rat amylin and the second layer of human amylin. Our results explain the weak amyloid-inhibiting properties of rat amylin and suggest that membrane leakage due to pore formation is responsible for the toxicity of rat amylin observed in a recent experiment. Together, our results put in question the use of rat amylin or the similar FDA approved drug pramlintide as an inhibitor of human amylin aggregation. They also point to mixed human-rat amylin fibril-like oligomers as possible model-systems for studies of amyloid formation that involve cross-species transmission. Public Library of Science 2014-05-08 /pmc/articles/PMC4014569/ /pubmed/24810618 http://dx.doi.org/10.1371/journal.pone.0097051 Text en © 2014 Berhanu, Hansmann http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Berhanu, Workalemahu M. Hansmann, Ulrich H. E. Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates |
title | Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates |
title_full | Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates |
title_fullStr | Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates |
title_full_unstemmed | Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates |
title_short | Inter-Species Cross-Seeding: Stability and Assembly of Rat - Human Amylin Aggregates |
title_sort | inter-species cross-seeding: stability and assembly of rat - human amylin aggregates |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014569/ https://www.ncbi.nlm.nih.gov/pubmed/24810618 http://dx.doi.org/10.1371/journal.pone.0097051 |
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