Proteomic analysis of highly prevalent amyloid A amyloidosis endemic to endangered island foxes.

Patricia M Gaffney,Aaron N Chang,Deana L Clifford,Majid Ghassemian,Christina Sigurdson,Denise M Imai,Linda Munson,Roman Sasik,Margarita Trejo,Timothy D O’Brien,Eliezer Masliah,Judith Coppinger

doi:10.1371/journal.pone.0113765

Abstract

Amyloid A (AA) amyloidosis is a debilitating, often fatal, systemic amyloid disease associated with chronic inflammation and persistently elevated serum amyloid A (SAA). Elevated SAA is necessary but not sufficient to cause disease and the risk factors for AA amyloidosis remain poorly understood. Here we identify an extraordinarily high prevalence of AA amyloidosis (34%) in a genetically isolated population of island foxes (Urocyon littoralis) with concurrent chronic inflammatory diseases. Amyloid deposits were most common in kidney (76%), spleen (58%), oral cavity (45%), and vasculature (44%) and were composed of unbranching, 10 nm in diameter fibrils. Peptide sequencing by mass spectrometry revealed that SAA peptides were dominant in amyloid-laden kidney, together with high levels of apolipoprotein E, apolipoprotein A-IV, fibrinogen-α chain, and complement C3 and C4 (false discovery rate ≤0.05). Reassembled peptide sequences showed island fox SAA as an 111 amino acid protein, most similar to dog and artic fox, with 5 unique amino acid variants among carnivores. SAA peptides extended to the last two C-terminal amino acids in 5 of 9 samples, indicating that near full length SAA was often present in amyloid aggregates. These studies define a remarkably prevalent AA amyloidosis in island foxes with widespread systemic amyloid deposition, a unique SAA sequence, and the co-occurrence of AA with apolipoproteins.

Highlights

Amyloid A (AA) amyloidosis is among the most common systemic amyloidoses in humans and animals and follows recurring episodes of inflammation and concurrently elevated serum amyloid A (SAA) protein levels [1,2,3,4]
These findings are reminiscent of humans with rheumatoid arthritis, in which 10 to 30% have AA amyloidosis [39,40,41]
Three of four SAA isoforms, Phe6-Gly7, Val6-Gly7, Leu6-Gly7, are predicted to have higher protein aggregation propensity as compared to Val6-Ser7, which could increase their risk for developing AA amyloidosis

Summary

Introduction

Amyloid A (AA) amyloidosis is among the most common systemic amyloidoses in humans and animals and follows recurring episodes of inflammation and concurrently elevated serum amyloid A (SAA) protein levels [1,2,3,4]. High SAA levels can trigger extracellular AA fibril formation [6], progressive amyloid deposition, and eventually organ dysfunction [7], most frequently renal failure [8]. SAA is a highly conserved protein composed of 104 to 112 amino acids [9] and human SAA is arranged in a four helix bundle that assembles into a hexamer [10]. The SAA hexamer binds high density lipoproteins (HDL) through at least two binding sites [10, 11]. SAA contains binding sites for glycosaminoglycans including heparan sulfate, which has been implicated in promoting SAA aggregation [10, 12, 13]

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Results

Conclusion