NDT Advance Access published online on May 8, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn231
Lysophospholipids induce the nucleation and extension of β2-microglobulin-related amyloid fibrils at a neutral pH
1 Department of Pathological Sciences, Division of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193 2 Department of General Medicine, Division of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193 3 Fujita Memorial Hospital, Fukui 910-0004 4 Institute for Protein Research, Osaka University, Osaka 565-0871 5 CREST, Japan Science and Technology Agency, Tokyo 103-0027, Japan
Correspondence and offprint requests to: Hironobu Naiki, Department of Pathological Sciences, Division of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan. Tel: +81-776-61-8320; Fax: +81-776-61-8123; E-mail: Naiki{at}u-fukui.ac.jp
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Abstract |
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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.
Keywords: amyloidosis; β2-microglobulin; lysophospholipid; thioflavin T
Received for publication: 10. 2.08
Accepted in revised form: 3. 4.08