Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis.

Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Research Abstract Details 

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Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Abstract Text:

Kana Tojo,Yoshiki Sekijima,Jeffery W Kelly,Shu-ichi Ikeda,

Transthyretin (TTR) tetramer dissociation, misfolding and misassembly are required for the process of amyloid fibril formation associated with familial amyloid polyneuropathy (FAP). Preferential stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Two NSAIDs, diflunisal and flufenamic acid, and trivalent chromium have this ability. Here, we investigated the feasibility of using these molecules for the treatment of FAP utilizing serum samples from 37 FAP patients with 10 different mutations. We demonstrated that the TTR heterotetramer structures in FAP patients serum are significantly less stable than that in normal subjects, indicating the instability of the variant TTR structure is a fundamental cause of TTR amyloidosis. We also demonstrated that therapeutic serum concentrations of diflunisal (100-200 microM) stabilized serum variant TTR tetramer better than those of flufenamic acid (35-70 microM). Trivalent chromium at levels obtained by oral supplementation did not stabilize TTR in a statistically significant fashion. Importantly, diflunisal increased serum TTR stability in FAP patients beyond the level of normal controls.

Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Publishing Authors By Initials

K Tojo,Y Sekijima,JW Kelly,S Ikeda,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: protein denaturation research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: protein denaturation research

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Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Neuroscience research

VOLUME: 56

Page Numbers: 441-9

Journal Abbreviation: Neurosci. Res.

ISSN: 0168-0102

DAY: 6

MONTH: 10

YEAR: 2006

Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Information

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LANGUAGE: eng

NlmUniqueID: 8500749

Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Keywords Mesh Terms:

KEYWORDS: Protein Denaturation

MESH TERMS: genetics

Chemical & Substance for Abstract: Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Information

Substance Name: Chromium

Registry Number: 7440-47-3

Grant and Affiliation Information for Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis.

AFFILIATION: Department of Neurology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.

Country: Ireland

AGENCY: United States NIDDK

GRANT: DK046335

ACRONYM: DK

MEDLINETA: Neurosci Res

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