Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition
Abstract
Significance Transthyretin (TTR) cardiac amyloidosis is characterized by the deposition of TTR amyloid fibrils in the heart. No therapy is currently available for wild-type cardiac amyloidosis. Hereditary cases are treated by liver transplantation, a crude form of gene therapy which replaces amyloidogenic mutant TTR by the more stable wild-type form, with the goal of halting further deposition and disease progression. However, wild-type TTR continues to deposit in the heart of many patients after the procedure. Until now, seeding of TTR fibril formation has not been demonstrated in vitro. We show that patient-extracted cardiac fibrils can seed both wild-type and mutant TTR fibril formation in vitro. This process can be inhibited by structure-based peptide inhibitors, thereby providing an alternative approach to therapy.
- Authors:
-
[1];
- Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095,, UCLA-DOE, University of California, Los Angeles, CA 90095,, Department of Biological Chemistry, University of California, Los Angeles, CA 90095,, Molecular Biology Institute, University of California, Los Angeles, CA 90095,
- Neuropsychiatric Institute (NPI)-Semel Institute, University of California, Los Angeles, CA 90024,
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202
- 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. https://doi.org/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. https://doi.org/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 = {Significance Transthyretin (TTR) cardiac amyloidosis is characterized by the deposition of TTR amyloid fibrils in the heart. No therapy is currently available for wild-type cardiac amyloidosis. Hereditary cases are treated by liver transplantation, a crude form of gene therapy which replaces amyloidogenic mutant TTR by the more stable wild-type form, with the goal of halting further deposition and disease progression. However, wild-type TTR continues to deposit in the heart of many patients after the procedure. Until now, seeding of TTR fibril formation has not been demonstrated in vitro. We show that patient-extracted cardiac fibrils can seed both wild-type and mutant TTR fibril formation in vitro. This process can be inhibited by structure-based peptide inhibitors, thereby providing an alternative approach to therapy.},
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}
}
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https://doi.org/10.1073/pnas.1805131115
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