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Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains
Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with protein misfolding and aggregation into amyloid fibrils. Increasing evidence suggests that soluble, low-molecular-weight aggregates play a key role in disease-associated toxicity. Within this population of aggregates,...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214208/ https://www.ncbi.nlm.nih.gov/pubmed/37186840 http://dx.doi.org/10.1073/pnas.2216234120 |
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author | Miller, Alyssa Wei, Jiapeng Meehan, Sarah Dobson, Christopher M. Welland, Mark E. Klenerman, David Vendruscolo, Michele Ruggeri, Francesco Simone Knowles, Tuomas P. J. |
author_facet | Miller, Alyssa Wei, Jiapeng Meehan, Sarah Dobson, Christopher M. Welland, Mark E. Klenerman, David Vendruscolo, Michele Ruggeri, Francesco Simone Knowles, Tuomas P. J. |
author_sort | Miller, Alyssa |
collection | PubMed |
description | Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with protein misfolding and aggregation into amyloid fibrils. Increasing evidence suggests that soluble, low-molecular-weight aggregates play a key role in disease-associated toxicity. Within this population of aggregates, closed-loop pore-like structures have been observed for a variety of amyloid systems, and their presence in brain tissues is associated with high levels of neuropathology. However, their mechanism of formation and relationship with mature fibrils have largely remained challenging to elucidate. Here, we use atomic force microscopy and statistical theory of biopolymers to characterize amyloid ring structures derived from the brains of AD patients. We analyze the bending fluctuations of protofibrils and show that the process of loop formation is governed by the mechanical properties of their chains. We conclude that ex vivo protofibril chains possess greater flexibility than that imparted by hydrogen-bonded networks characteristic of mature amyloid fibrils, such that they are able to form end-to-end connections. These results explain the diversity in the structures formed from protein aggregation and shed light on the links between early forms of flexible ring-forming aggregates and their role in disease. |
format | Online Article Text |
id | pubmed-10214208 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-102142082023-05-27 Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains Miller, Alyssa Wei, Jiapeng Meehan, Sarah Dobson, Christopher M. Welland, Mark E. Klenerman, David Vendruscolo, Michele Ruggeri, Francesco Simone Knowles, Tuomas P. J. Proc Natl Acad Sci U S A Biological Sciences Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with protein misfolding and aggregation into amyloid fibrils. Increasing evidence suggests that soluble, low-molecular-weight aggregates play a key role in disease-associated toxicity. Within this population of aggregates, closed-loop pore-like structures have been observed for a variety of amyloid systems, and their presence in brain tissues is associated with high levels of neuropathology. However, their mechanism of formation and relationship with mature fibrils have largely remained challenging to elucidate. Here, we use atomic force microscopy and statistical theory of biopolymers to characterize amyloid ring structures derived from the brains of AD patients. We analyze the bending fluctuations of protofibrils and show that the process of loop formation is governed by the mechanical properties of their chains. We conclude that ex vivo protofibril chains possess greater flexibility than that imparted by hydrogen-bonded networks characteristic of mature amyloid fibrils, such that they are able to form end-to-end connections. These results explain the diversity in the structures formed from protein aggregation and shed light on the links between early forms of flexible ring-forming aggregates and their role in disease. National Academy of Sciences 2023-05-15 2023-05-23 /pmc/articles/PMC10214208/ /pubmed/37186840 http://dx.doi.org/10.1073/pnas.2216234120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Miller, Alyssa Wei, Jiapeng Meehan, Sarah Dobson, Christopher M. Welland, Mark E. Klenerman, David Vendruscolo, Michele Ruggeri, Francesco Simone Knowles, Tuomas P. J. Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
title | Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
title_full | Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
title_fullStr | Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
title_full_unstemmed | Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
title_short | Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
title_sort | formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214208/ https://www.ncbi.nlm.nih.gov/pubmed/37186840 http://dx.doi.org/10.1073/pnas.2216234120 |
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