Lysophospholipids induce the nucleation and extension of β2-microglobulin-related amyloid fibrils at a neutral pH
Lysophospholipids induce the nucleation and extension of β2-microglobulin-related amyloid fibrils at a neutral pH
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DOI：
10.1093/ndt/gfn231
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发表时间：
2008-10-01
影响因子：
6.1
通讯作者：
Naiki, Hironobu
中科院分区：
文献类型：
--
作者：
Ookoshi, Tadakazu;Hasegawa, Kazuhiro;Naiki, Hironobu
背景。在β(2)-微球蛋白相关(Aβ2M)淀粉样变性中，β(2)-微球蛋白(β2-m)的部分解折叠被认为是其在体内组装成Aβ2M淀粉样原纤维的先决条件。低浓度的十二烷基硫酸钠在体外诱导β2-m部分解折叠成淀粉样蛋白构象异构体，并随后形成淀粉样原纤维，但在接近生理条件下诱导它们的生物分子尚未确定。方法。我们使用硫黄素 T 荧光光谱、圆二色光谱和电子显微镜研究了一些溶血磷脂在中性 pH 条件下对 A beta 2M 淀粉样原纤维的成核、延伸和稳定的影响。我们还测量了 103 名血液透析患者和 14 名健康受试者的血浆溶血磷脂浓度，并检查了尿毒症和正常血浆对中性 pH 值下 Aβ2M 淀粉样原纤维稳定性的影响。结果。一些溶血磷脂，特别是溶血磷脂酸 (LPA)，不仅诱导 A β 2M 淀粉样蛋白原纤维的延伸，而且通过将 β 2-m 的紧凑结构部分展开为淀粉样蛋白形成构象异构体以及稳定延伸的原纤维，在中性 pH 下诱导由 β 2-m 单体形成 A β 2M 淀粉样蛋白原纤维。血液透析患者血浆 LPA 浓度显着高于健康受试者。此外，LPA 浓度最高的尿毒症血浆稳定 Aβ2M 淀粉样原纤维的能力明显强于正常血浆。另一方面，在正常血浆中简单添加LPA并不能增强原纤维稳定活性。结论。这些结果表明溶血磷脂在 A beta 2M 淀粉样变性的发展中可能发挥作用。
Background. In beta(2)-microglobulin-related (A beta 2M) amyloidosis, partial unfolding of beta(2)-microglobulin (beta 2-m) is believed to be prerequisite to its assembly into A beta 2M amyloid fibrils in vivo. Low concentrations of sodium dodecyl sulfate induce partial unfolding of beta 2-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 A beta 2M 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 A beta 2M amyloid fibrils at a neutral pH.Results. Some lysophospholipids, especially lysophosphatidic acid (LPA), induced not only the extension of A beta 2M amyloid fibrils but also the formation of A beta 2M amyloid fibrils from the beta 2-m monomer at a neutral pH, by partially unfolding the compact structure of beta 2-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 A beta 2M 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 A beta 2M amyloidosis.