Inhibiting transthyretin amyloid fibril formation via protein stabilization

Greta J. Miroy, Zhihong Lai, Hilal A. Lashuel, Scott A. Peterson, Candace Strang, Jeffery W. Kelly

Research output: Contribution to journalArticle

274 Citations (Scopus)

Abstract

Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 μM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation. In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism. Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine. These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases. This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis-i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.

Original languageEnglish
Pages (from-to)15051-15056
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number26
DOIs
Publication statusPublished - 24 Dec 1996
Externally publishedYes

Fingerprint

Prealbumin
Amyloid
Familial Amyloid Neuropathies
Proteins
Amyloidosis
Thyroxine
Amyloidogenic Proteins
Ligands

Keywords

  • familial amyloid polyneuropathy
  • therapeutic strategy

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inhibiting transthyretin amyloid fibril formation via protein stabilization. / Miroy, Greta J.; Lai, Zhihong; Lashuel, Hilal A.; Peterson, Scott A.; Strang, Candace; Kelly, Jeffery W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 26, 24.12.1996, p. 15051-15056.

Research output: Contribution to journalArticle

Miroy, Greta J. ; Lai, Zhihong ; Lashuel, Hilal A. ; Peterson, Scott A. ; Strang, Candace ; Kelly, Jeffery W. / Inhibiting transthyretin amyloid fibril formation via protein stabilization. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 26. pp. 15051-15056.
@article{fd8fe7a5fd0145ec936e472d48ec741c,
title = "Inhibiting transthyretin amyloid fibril formation via protein stabilization",
abstract = "Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 μM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation. In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism. Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine. These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases. This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis-i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.",
keywords = "familial amyloid polyneuropathy, therapeutic strategy",
author = "Miroy, {Greta J.} and Zhihong Lai and Lashuel, {Hilal A.} and Peterson, {Scott A.} and Candace Strang and Kelly, {Jeffery W.}",
year = "1996",
month = "12",
day = "24",
doi = "10.1073/pnas.93.26.15051",
language = "English",
volume = "93",
pages = "15051--15056",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "26",

}

TY - JOUR

T1 - Inhibiting transthyretin amyloid fibril formation via protein stabilization

AU - Miroy, Greta J.

AU - Lai, Zhihong

AU - Lashuel, Hilal A.

AU - Peterson, Scott A.

AU - Strang, Candace

AU - Kelly, Jeffery W.

PY - 1996/12/24

Y1 - 1996/12/24

N2 - Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 μM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation. In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism. Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine. These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases. This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis-i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.

AB - Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 μM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation. In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism. Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine. These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases. This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis-i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.

KW - familial amyloid polyneuropathy

KW - therapeutic strategy

UR - http://www.scopus.com/inward/record.url?scp=0030447882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030447882&partnerID=8YFLogxK

U2 - 10.1073/pnas.93.26.15051

DO - 10.1073/pnas.93.26.15051

M3 - Article

C2 - 8986762

AN - SCOPUS:0030447882

VL - 93

SP - 15051

EP - 15056

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

ER -