Skip to main content
placeholder image

Human pregnancy zone protein stabilizes misfoldedproteins including preeclampsia- and Alzheimer’s-associated amyloid beta peptide

Journal Article


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.

Authors


  •   Cater, Jordan (external author)
  •   Kumita, Janet R. (external author)
  •   Abdallah, Rafaa (external author)
  •   Zhao, Guomao (external author)
  •   Bernardo-Gancedo, Ana (external author)
  •   Henry, Amanda (external author)
  •   Winata, Wendy (external author)
  •   Chi, Mengna (external author)
  •   Grenyer, Brin F. S.
  •   Townsend, Michelle L.
  •   Ranson, Marie
  •   Buhimschi, Catalin (external author)
  •   Charnock-Jones, D (external author)
  •   Dobson, Christopher M. (external author)
  •   Mark R Wilson
  •   Buhimschi, Irina (external author)
  •   Wyatt, Amy R.

Publication Date


  • 2019

Citation


  • 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 misfoldedproteins 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.

Scopus Eid


  • 2-s2.0-85063937163

Number Of Pages


  • 9

Start Page


  • 6101

End Page


  • 6110

Volume


  • 116

Issue


  • 13

Place Of Publication


  • United States

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.

Authors


  •   Cater, Jordan (external author)
  •   Kumita, Janet R. (external author)
  •   Abdallah, Rafaa (external author)
  •   Zhao, Guomao (external author)
  •   Bernardo-Gancedo, Ana (external author)
  •   Henry, Amanda (external author)
  •   Winata, Wendy (external author)
  •   Chi, Mengna (external author)
  •   Grenyer, Brin F. S.
  •   Townsend, Michelle L.
  •   Ranson, Marie
  •   Buhimschi, Catalin (external author)
  •   Charnock-Jones, D (external author)
  •   Dobson, Christopher M. (external author)
  •   Mark R Wilson
  •   Buhimschi, Irina (external author)
  •   Wyatt, Amy R.

Publication Date


  • 2019

Citation


  • 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 misfoldedproteins 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.

Scopus Eid


  • 2-s2.0-85063937163

Number Of Pages


  • 9

Start Page


  • 6101

End Page


  • 6110

Volume


  • 116

Issue


  • 13

Place Of Publication


  • United States