Protein profiling of isolated uterine AA amyloidosis causing fetal death in goats

Patricia M. Gaffney, Bradd Barr, Joan D Rowe, Cyrus Bett, Ioannis Drygiannakis, Federico Giannitti, Margarita Trejo, Majid Ghassemian, Patrice Martin, Eliezer Masliah, Christina J. Sigurdson

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Pathologic amyloid accumulates in the CNS or in peripheral organs, yet the mechanism underlying the targeting of systemic amyloid deposits is unclear. Serum amyloid A (SAA) 1 and 2 are produced predominantly by the liver and form amyloid most commonly in the spleen, liver, and kidney. In contrast, SAA3 is produced primarily extrahepatically and has no causal link to amyloid formation. Here, we identified 8 amyloidosis cases with amyloid composed of SAA3 expanding the uterine wall of goats with near-term fetuses. Uterine amyloid accumulated in the endometrium, only at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal ischemia and death. No other organ contained amyloid. SAA3 mRNA levels in the uterine endometrium were as high as SAA2 in the liver, yet mass spectrometry of the insoluble uterine peptides identified SAA3 as the predominant protein, and not SAA1 or SAA2. These findings suggest that high local SAA3 production led to deposition at this unusual site. Although amyloid A (AA) amyloid deposits typically consist of an N-terminal fragment of SAA1 or SAA2, here, abundant C-terminal peptides indicated that the uterine amyloid was largely composed of full-length SAA3. The exclusive deposition of SAA3 amyloid in the uterus, together with elevated uterine SAA3 transcripts, suggests that the uterine amyloid deposits were due to locally produced SAA3. This is the first report of SAA3 as a cause of amyloidosis and of AA amyloid deposited exclusively in the uterus.

Original languageEnglish (US)
Pages (from-to)911-919
Number of pages9
JournalFASEB Journal
Volume29
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • Amyloid
  • Mass spectrometry
  • Protein misfolding

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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  • Cite this

    Gaffney, P. M., Barr, B., Rowe, J. D., Bett, C., Drygiannakis, I., Giannitti, F., Trejo, M., Ghassemian, M., Martin, P., Masliah, E., & Sigurdson, C. J. (2015). Protein profiling of isolated uterine AA amyloidosis causing fetal death in goats. FASEB Journal, 29(3), 911-919. https://doi.org/10.1096/fj.14-256081