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

Lorena Saelices, Kevin Chung, Ji H. Lee, Whitaker Cohn, Julian P. Whitelegge, Merrill Benson, David S. Eisenberg

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E6741-E6750
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number29
DOIs
StatePublished - Jul 17 2018

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Prealbumin
Amyloid
Seeds
Protein Precursors
Liver
Standard of Care
Liver Transplantation
Genes
Blood Proteins
Carrier Proteins
Peptides
Growth

Keywords

  • Amyloid
  • Amyloidosis
  • Cardiomyopathy
  • Seeding
  • Transthyretin

ASJC Scopus subject areas

  • General

Cite this

Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. / Saelices, Lorena; Chung, Kevin; Lee, Ji H.; Cohn, Whitaker; Whitelegge, Julian P.; Benson, Merrill; Eisenberg, David S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 29, 17.07.2018, p. E6741-E6750.

Research output: Contribution to journalArticle

Saelices, Lorena ; Chung, Kevin ; Lee, Ji H. ; Cohn, Whitaker ; Whitelegge, Julian P. ; Benson, Merrill ; Eisenberg, David S. / Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 29. pp. E6741-E6750.
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