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Title: Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

Abstract

Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutant TTR gene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.

Authors:
ORCiD logo; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1457595
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 29; Journal ID: ISSN 0027-8424
Publisher:
Proceedings of the National Academy of Sciences
Country of Publication:
United States
Language:
English

Citation Formats

Saelices, Lorena, Chung, Kevin, Lee, Ji H., Cohn, Whitaker, Whitelegge, Julian P., Benson, Merrill D., and Eisenberg, David S. Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. United States: N. p., 2018. Web. doi:10.1073/pnas.1805131115.
Saelices, Lorena, Chung, Kevin, Lee, Ji H., Cohn, Whitaker, Whitelegge, Julian P., Benson, Merrill D., & Eisenberg, David S. Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. United States. doi:10.1073/pnas.1805131115.
Saelices, Lorena, Chung, Kevin, Lee, Ji H., Cohn, Whitaker, Whitelegge, Julian P., Benson, Merrill D., and Eisenberg, David S. Thu . "Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition". United States. doi:10.1073/pnas.1805131115.
@article{osti_1457595,
title = {Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition},
author = {Saelices, Lorena and Chung, Kevin and Lee, Ji H. and Cohn, Whitaker and Whitelegge, Julian P. and Benson, Merrill D. and Eisenberg, David S.},
abstractNote = {Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutant TTR gene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.},
doi = {10.1073/pnas.1805131115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 29,
volume = 115,
place = {United States},
year = {2018},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1073/pnas.1805131115

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Cited by: 6 works
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Works referenced in this record:

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