Abstract
BackgroundSerum amyloid P component (SAP) is a glycoprotein that is universally found associated with different types of amyloid deposits. It has been suggested that it stabilizes amyloid fibrils and therefore protects them from proteolytic degradation.Methodology/Principal FindingsIn this paper, we show that SAP binds not only to mature amyloid fibrils but also to early aggregates of amyloidogenic mutants of the plasma protein transthyretin (TTR). It does not inhibit fibril formation of TTR mutants, which spontaneously form amyloid in vitro at physiological pH. We found that SAP prevents cell death induced by mutant TTR, while several other molecules that are also known to decorate amyloid fibrils do not have such effect. Using a Drosophila model for TTR-associated amyloidosis, we found a new role for SAP as a protective factor in inhibition of TTR-induced toxicity. Overexpression of mutated TTR leads to a neurological phenotype with changes in wing posture. SAP-transgenic flies were crossed with mutated TTR-expressing flies and the results clearly confirmed a protective effect of SAP on TTR-induced phenotype, with an almost complete reduction in abnormal wing posture. Furthermore, we found in vivo that binding of SAP to mutated TTR counteracts the otherwise detrimental effects of aggregation of amyloidogenic TTR on retinal structure.Conclusions/SignificanceTogether, these two approaches firmly establish the protective effect of SAP on TTR-induced cell death and degenerative phenotypes, and suggest a novel role for SAP through which the toxicity of early amyloidogenic aggregates is attenuated.
Highlights
Serum amyloid P component (SAP) is a plasma glycoprotein
The biological role of SAP is only partly known. It binds in a calcium-dependent way to molecular arrays such as DNA, chromatin, histones, and phosphoethanolamine-containing membranes, suggesting that it has a function in clearance of late apoptotic cells [5,6,7,8,9,10]
In order to investigate whether binding of SAP occurs early, before the fibrils are formed, we subjected recombinant TTRs to aggregation at physiological pH in the presence of SAP for 4 days at 37uC
Summary
Serum amyloid P component (SAP) is a plasma glycoprotein. It is a member of the pentraxin superfamily of calciumdependent ligand binding lectin proteins. Another member is Creactive protein (CRP), the classical acute-phase reactant in humans [1,2]. The biological role of SAP is only partly known. It binds in a calcium-dependent way to molecular arrays such as DNA, chromatin, histones, and phosphoethanolamine-containing membranes, suggesting that it has a function in clearance of late apoptotic cells [5,6,7,8,9,10]. It has been suggested that it stabilizes amyloid fibrils and protects them from proteolytic degradation
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