title: Thiol compounds inhibit the formation of amyloid fibrils by beta 2-microglobulin at neutral pH.
abstract: Dialysis-related amyloidosis frequently develops in patients undergoing long-term hemodialysis, in which the major component of fibrils is beta(2)-microglobulin (beta2-m). To prevent the disease, it is important to stop the formation of fibrils. beta2-m has one disulfide bond, which stabilizes the native structure, and amyloid fibrils. Here, the effects of reductants (i.e., dithiothreitol and cysteine) on the formation of beta2-m amyloid fibrils were examined at neutral pH. Fibrils were generated by three methods: seed-dependent, ultrasonication-induced, and salt-and-heat-induced fibrillation. Thioflavin T fluorescence, electron microscopy, and far-UV circular dichroism revealed that the addition of reductants significantly inhibits seed-dependent and ultrasonication-induced fibrillation. For salt-and-heat-induced fibrillation, where the solution of beta2-m was strongly agitated, formation of amyloid fibrils was markedly reduced in the presence of reductants, although a small number of fibrils formed even after the reduction of the disulfide bond. The results suggest that reductants such as cysteine and dithiothreitol would be useful for preventing the formation of beta2-m amyloid fibrils under physiological conditions.
authors.affiliation: Institute for Protein Research, Osaka University, and CREST, Japan Science and Technology Agency, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yagi
authors.forename: Daisaku
authors.initials: D
authors.lastname: Ozawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasahara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Naiki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors*; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D019163:Reducing Agents / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology*; D001613:beta 2-Microglobulin / Q000378:metabolism*
chemical_list: D000682:Amyloid; D019163:Reducing Agents; D013438:Sulfhydryl Compounds; D001613:beta 2-Microglobulin