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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,...

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Autores principales: Miller, Alyssa, Wei, Jiapeng, Meehan, Sarah, Dobson, Christopher M., Welland, Mark E., Klenerman, David, Vendruscolo, Michele, Ruggeri, Francesco Simone, Knowles, Tuomas P. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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