In vivo stabilization of mutant human transthyretin in transgenic mice

Clement E. Tagoe, Natàlia Reixach, Linsey Friske, David Mustra, David French, Gloria Gallo, Joel N. Buxbaum

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Transthyretin (TTR) is a 55 kD homotetrameric serum protein transporter of retinol binding protein charged with retinol and thyroxine (T4). The highly amyloidogenic human TTR variant in which leucine at position 55 is replaced by proline (L55P TTR) is responsible for aggressive fatal amyloidosis with peripheral and autonomic neuropathy, cardiomyopathy and nephropathy. Mice bearing one or two copies of a 19.2 kB human genomic fragment containing the entire coding sequence and the known control regions of the L55P TTR transgene, failed to develop TTR amyloidosis even though their sera contained mutant human TTR. The frequency of TTR tissue deposition was increased when the L55P TTR transgene was bred onto a murine TTR-null background. Denaturation of sera from the transgenic animals and murine TTR-knockouts expressing the human L55P TTR transgene revealed that the TTR tetramer was much more stable in the presence of the murine protein because the TTR circulates as hybrid human/murine heterotetramers. Intraperitoneal administration of diflunisal, a non-steroidal anti-inflammatory drug that binds to TTR in its T4-binding site and inhibits fibril formation in vitro, to human L55P TTR transgenic animals in which the murine TTR gene had been silenced, also stabilizes the circulating mutant protein to in vitro urea denaturation.

Original languageEnglish (US)
Pages (from-to)227-236
Number of pages10
JournalAmyloid
Volume14
Issue number3
DOIs
StatePublished - 2007
Externally publishedYes

Fingerprint

Prealbumin
Transgenic Mice
Transgenes
Genetically Modified Animals
Diflunisal
Retinol-Binding Proteins
Peripheral Nervous System Diseases
Amyloidosis
Mutant Proteins
Serum
Vitamin A
Cardiomyopathies
Thyroxine
Proline
Leucine

Keywords

  • Amyloidosis
  • Diflunisal
  • FAP
  • Heterotetramers
  • Transgenics
  • Transthyretin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Tagoe, C. E., Reixach, N., Friske, L., Mustra, D., French, D., Gallo, G., & Buxbaum, J. N. (2007). In vivo stabilization of mutant human transthyretin in transgenic mice. Amyloid, 14(3), 227-236. https://doi.org/10.1080/13506120701464396

In vivo stabilization of mutant human transthyretin in transgenic mice. / Tagoe, Clement E.; Reixach, Natàlia; Friske, Linsey; Mustra, David; French, David; Gallo, Gloria; Buxbaum, Joel N.

In: Amyloid, Vol. 14, No. 3, 2007, p. 227-236.

Research output: Contribution to journalArticle

Tagoe, CE, Reixach, N, Friske, L, Mustra, D, French, D, Gallo, G & Buxbaum, JN 2007, 'In vivo stabilization of mutant human transthyretin in transgenic mice', Amyloid, vol. 14, no. 3, pp. 227-236. https://doi.org/10.1080/13506120701464396
Tagoe, Clement E. ; Reixach, Natàlia ; Friske, Linsey ; Mustra, David ; French, David ; Gallo, Gloria ; Buxbaum, Joel N. / In vivo stabilization of mutant human transthyretin in transgenic mice. In: Amyloid. 2007 ; Vol. 14, No. 3. pp. 227-236.
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