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- Title
Lysophospholipids induce the nucleation and extension of {beta}2-microglobulin-related amyloid fibrils at a neutral pH.
- Authors
Tadakazu Ookoshi; Kazuhiro Hasegawa; Yumiko Ohhashi; Hideki Kimura; Naoki Takahashi; Haruyoshi Yoshida; Ryoichi Miyazaki; Yuji Goto; Hironobu Naiki
- Abstract
Background. In β2-microglobulin-related (Aβ2M) amyloidosis, partial unfolding of β2-microglobulin (β2-m) is believed to be prerequisite to its assembly into Aβ2M amyloid fibrils in vivo. Low concentrations of sodium dodecyl sulfate induce partial unfolding of β2-m to an amyloidogenic conformer and subsequent amyloid fibril formation in vitro, but the biological molecules that induce them under near-physiological conditions have not been determined. Methods. We investigated the effect of some lysophospholipids on the nucleation, extension and stabilization of Aβ2M amyloid fibrils at a neutral pH, using fluorescence spectroscopy with thioflavin T, circular dichroism spectroscopy and electron microscopy. We also measured plasma concentrations of lysophospholipids in 103 haemodialysis patients and 14 healthy subjects and examined the effect of uraemic and normal plasmas on the stabilization of Aβ2M amyloid fibrils at a neutral pH. Results. Some lysophospholipids, especially lysophosphatidic acid (LPA), induced not only the extension of Aβ2M amyloid fibrils but also the formation of Aβ2M amyloid fibrils from the β2-m monomer at a neutral pH, by partially unfolding the compact structure of β2-m to an amyloidogenic conformer as well as stabilizing the extended fibrils. Haemodialysis patients had significantly higher plasma concentrations of LPA than healthy subjects. Furthermore, uraemic plasmas with the highest ranking LPA concentrations stabilized Aβ2M amyloid fibrils significantly more potently than normal plasmas. On the other hand, simple addition of LPA to normal plasma did not enhance the fibril stabilizing activity. Conclusions. These results suggest a possible role of lysophospholipids in the development of Aβ2M amyloidosis.
- Subjects
NUCLEATION; AMYLOID; HEMODIALYSIS patients; AMYLOIDOSIS; FLUORESCENCE spectroscopy; PH effect; GLOBULINS; DENATURATION of proteins
- Publication
Nephrology Dialysis Transplantation, 2008, Vol 23, Issue 10, p3247
- ISSN
0931-0509
- Publication type
Article
- DOI
10.1093/ndt/gfn231