3-nitrotyrosine and Amyloid-Neuropathies--Familial

Amyloid deposits consist of protein fibrils and amorphous material, and this deposition is related to oxidative stress. Previously, we demonstrated the presence of high-density lipoproteins and/or lipids in amyloid deposits of familial amyloid polyneuropathy patients. In this study, the presence of myeloperoxidase (MPO) in amyloid deposits was demonstrated using immunohistochemical staining. In contrast, normal surrounding tissues were consistently negative for MPO. Nitrotyrosine was present in amyloid deposits after being exposed to the MPO/H2O2/NO(-) system by immunohistochemical staining, and the oxide mediated modification of serum transthyretin (TTR) was observed upon exposure to the MPO/H2O2 system using two-dimensional gel electrophoresis and TTR Western blotting. This observation revealed that the TTR amyloid deposits and serum TTR were oxidized by the MPO/H2O2/NO(-) system. Nitric oxide-mediated modification of TTR may play a role in amyloidogenesis in vivo.

Topics: Adult; Amyloid; Amyloid Neuropathies, Familial; Female; Humans; Hydrogen Peroxide; Lipoproteins, HDL; Middle Aged; Mutation; Nitric Oxide; Peroxidase; Prealbumin; Tyrosine

Tauroursodeoxycholic acid (TUDCA) is a unique natural compound that acts as a potent anti-apoptotic and anti-oxidant agent, reducing cytotoxicity in several neurodegenerative diseases. Since oxidative stress, apoptosis and inflammation are associated with transthyretin (TTR) deposition in Familial Amyloidotic Polyneuropathy (FAP), we investigated the possible TUDCA therapeutical application in this disease. We show by semi-quantitative immunohistochemistry and western blotting that administration of TUDCA to a transgenic mouse model of FAP decreased apoptotic and oxidative biomarkers usually associated with TTR deposition, namely the ER stress markers BiP and eIF2alpha, the Fas death receptor and oxidation products such as 3-nitrotyrosine. Most important, TUDCA treatment significantly reduced TTR toxic aggregates in as much as 75%. Since TUDCA has no effect on TTR aggregation "in vitro", this finding points for the "in vivo" modulation of TTR aggregation by cellular responses, such as by oxidative stress, ER stress and apoptosis and prompts for the use of this safe drug in prophylactic and therapeutic measures in FAP.

Topics: Amyloid Neuropathies, Familial; Animals; Apoptosis; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; fas Receptor; Gastrointestinal Tract; Heat-Shock Proteins; Humans; Immunohistochemistry; Methionine; Mice; Mice, Transgenic; Molecular Chaperones; Mutant Proteins; Mutation; Oxidation-Reduction; Prealbumin; Protein Structure, Quaternary; Taurochenodeoxycholic Acid; Thermodynamics; Tyrosine