Abstract
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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.