Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's- associated amyloid beta peptide

Authors

Jordan Cater, University of WollongongFollow
Janet R. Kumita, University of CambridgeFollow
Rafaa Abdallah, University of Wollongong
Guomao Zhao, The Research Institute of Nationwide Children's Hospital
Ana Bernardo-Gancedo, University of Cambridge
Amanda Henry, University of New South Wales, St. George Hospital
Wendy Winata, University of New South Wales
Mengna Chi, University of WollongongFollow
Brin F. S Grenyer, University of WollongongFollow
Michelle L. Townsend, University of WollongongFollow
Marie Ranson, University of WollongongFollow
Catalin Buhimschi, Ohio State University
D Charnock-Jones, University of Cambridge
Christopher M. Dobson, University of CambridgeFollow
Mark R. Wilson, University of WollongongFollow
Irina Buhimschi, Ohio State University, The Research Institute at Nationwide Children’s Hospital
Amy R. Wyatt, University of Wollongong, Flinders UniversityFollow

RIS ID

134656

Publication Details

Cater, J. H., Kumita, J. R., Abdallah, R. Zeineddine., Zhao, G., Bernardo-Gancedo, A., Henry, A., Winata, W., Chi, M., Grenyer, B. S. F., Townsend, M. L., Ranson, M., Buhimschi, C. S., Charnock-Jones, D. Stephen., Dobson, C. M., Wilson, M. R., Buhimschi, I. A. & Wyatt, A. R. (2019). Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide. Proceedings Of The National Academy Of Sciences Of The United States Of America, 116 (13), 6101-6110.

Abstract

Protein misfolding underlies the pathology of a large number of human disorders, many of which are age-related. An exception to this is preeclampsia, a leading cause of pregnancy-associated morbidity and mortality in which misfolded proteins accumulate in body fluids and the placenta. We demonstrate that pregnancy zone protein (PZP), which is dramatically elevated in maternal plasma during pregnancy, efficiently inhibits in vitro the aggregation of misfolded proteins, including the amyloid beta peptide (Aβ) that is implicated in preeclampsia as well as with Alzheimer's disease. The mechanism by which this inhibition occurs involves the formation of stable complexes between PZP and monomeric Aβ or small soluble Aβ oligomers formed early in the aggregation pathway. The chaperone activity of PZP is more efficient than that of the closely related protein alpha-2-macroglobulin (α₂M), although the chaperone activity of α₂M is enhanced by inducing its dissociation into PZP-like dimers. By immunohistochemistry analysis, PZP is found primarily in extravillous trophoblasts in the placenta. In severe preeclampsia, PZP-positive extravillous trophoblasts are adjacent to extracellular plaques containing Aβ, but PZP is not abundant within extracellular plaques. Our data support the conclusion that the up-regulation of PZP during pregnancy represents a major maternal adaptation that helps to maintain extracellular proteostasis during gestation in humans. We propose that overwhelming or disrupting the chaperone function of PZP could underlie the accumulation of misfolded proteins in vivo. Attempts to characterize extracellular proteostasis in pregnancy will potentially have broad-reaching significance for understanding disease-related protein misfolding.