sodium-dodecyl-sulfate and Amyloidosis

beta(2)-Microglobulin-related (Abeta(2)M) amyloidosis is a serious complication in patients on long-term dialysis, and partial unfolding of beta(2)-microglobulin (beta(2)-m) is believed to be prerequisite to its assembly into Abeta(2)M amyloid fibrils. Many kinds of amyloid-associated molecules (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Abeta(2)M amyloidosis. The formation of Abeta(2)M amyloid fibrils in vitro was first observed at low pH (2.0-3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of Abeta(2)M amyloid fibrils at a neutral pH, inducing partial unfolding of beta(2)-m and stabilization of the fibrils. Moreover, apoE, GAGs and PGs were found to stabilize Abeta(2)M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured beta(2)-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of beta(2)-m and amyloid fibrils will have significant effects on the deposition of Abeta(2)M amyloid fibrils.

Topics: Amyloid; Amyloidosis; Animals; Apolipoproteins E; beta 2-Microglobulin; Glycosaminoglycans; Humans; Hydrogen-Ion Concentration; Kinetics; Mice; Protein Structure, Quaternary; Proteoglycans; Sodium Dodecyl Sulfate; Trifluoroethanol

In familial amyloid cardiomyopathy of Danish origin, the amyloid microfibrils contain a mutant transthyretin (TTR) with a methionine-for-leucine substitution at the molecular position 111. We studied the possible occurrence of this variant TTR-Met111 in serum from afflicted as well as nonafflicted family members and their offspring, in order to define its possible role as predictor of the disease and to describe its mode of inheritance.. Stored, frozen serum samples obtained from 1959 through 1960 from 36 of 40 living members of the kindred were analyzed. The method employed to detect the abnormal TTR was based on the electrophoretic separation of fragments produced by cyanogen bromide cleavage at the two methionine sites.. All sera from family members with amyloid cardiomyopathy contained the variant transthyretin TTR-Met111 as did sera from half of their offspring. In contrast, nonafflicted family members and their offspring were seronegative for TTR-Met111. Three cousins from the second generation died between 1980 and 1986 of amyloid cardiomyopathy. The presence of variant TTR-Met111 preceded their deaths by 20 to 26 years.. The occurrence in serum of the mutant transthyretin TTR-Met111 is linked to the occurrence of amyloid cardiomyopathy in patients and their offspring, while unafflicted branches of the family are negative for the variant protein. That the occurrence in serum of TTR-Met111 precedes the onset of clinical amyloid cardiomyopathy by several decades makes the variant TTR a marker for the disease. The distribution of afflicted family members and seropositivity for the variant TTR shows an autosomal dominant mode of inheritance.. The results make possible early detection of potential patients and provide tools for genetic counseling. Cardiac transplantation may provide a new therapeutic option.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Cardiomyopathies; Denmark; Electrophoresis, Polyacrylamide Gel; Female; Heterozygote; Humans; Male; Methionine; Middle Aged; Mutation; Pedigree; Peptide Fragments; Prealbumin; Sodium Dodecyl Sulfate

Topics: Amino Acids; Amyloid; Amyloidosis; Birefringence; Carbohydrates; Chromatography, Thin Layer; Congo Red; Electrophoresis, Polyacrylamide Gel; Glycine; Humans; Liver; Macromolecular Substances; Nitrogen; Peptides; Protein Conformation; Sodium Dodecyl Sulfate; Spectrophotometry; Spleen; Ultracentrifugation; Ultrafiltration; Urea