Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis.
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.
Tojo
Kana
K
Department of Neurology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
Sekijima
Yoshiki
Y
Kelly
Jeffery W
JW
Ikeda
Shu-ichi
S
D000328:Adult; D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002857:Chromium / Q000494:pharmacology; D004061:Diflunisal / Q000494:pharmacology*; D005260:Female; D005439:Flufenamic Acid / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011228:Prealbumin / Q000096:biosynthesis* / Q000235:genetics*; D011489:Protein Denaturation
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011228:Prealbumin; D002857:Chromium; D005439:Flufenamic Acid; D004061:Diflunisal; D007501:Iron