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

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.

<p>Prognostic Significance of Pregnancy Zone Protein and Its Correlation with Immune Infiltrates in Hepatocellular Carcinoma</p>

“…Cater et al found that PZP could efficiently inhibit the aggregation of misfolded proteins including amyloid beta peptide and maintain protein homeostasis during pregnancy, indicating that PZP might play a potential role in the development of preeclampsia and Alzheimer's disease. 4 Furthermore, as a powerful T cell immunosuppressant for preventing rejection of the fetal allograft during pregnancy, PZP was associated with airway infection, disease severity in bronchiectasis during chronic airway inflammation. 15 However, in the previous studies, the relationship between PZP expression and tumor, especially HCC was not reported.…”

“…The concentration of PZP in womens' blood plasma is detectable a few weeks postconception, then can reach up to 3 mg/ mL in some individuals by 30 weeks of gestation, and finally return to near zero immediately postpartum. 4 As a broad-spectrum immunosuppressant with antiproteinase activity, knockdown of PZP may fail to prevent rejection of heart allografts and increase susceptibility to viral infection in mice. 5 Furthermore, PZP may have been shown to play an important role in modulating T cell activation and IL-2 production.…”

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

“…Recent studies have shown that misfolded proteins accumulate in the urine, serum, and the placenta of women with PE [99][100][101][102][103][104]. Indeed, proteins are vulnerable to misfolding because of changes in genetic and environmental factors [105] (Figure 1).…”

“…It was proposed that the high levels of PZP during pregnancy represent a maternal adaptation counteracting protein aggregation, for example via the formation of stable complexes between PZP and Aβ. PLZ, which is normally present as a dimer in biological fluids, is known to inhibit heat-induced protein aggregation [103] and could be a candidate for the efficient anti-aggregation chaperone similar to dimeric α2M.…”

Aging-Related and Gender Specific Albumin Misfolding in Alzheimer’s Disease

“…Some misfolded proteins have been shown to be toxic to cells and have been linked to numerous diseases including neurodegenerative diseases (most prominently AD, Parkinson's disease, and late-onset multiple sclerosis), type 2 diabetes, certain forms of heart disease, cancers, and cataracts [8][9][10]. In addition, although not related to advance age, misfolded proteins have been found to be associated with preeclampsia [11,12]. While oxidative stress and inflammation may play important roles in protein structural modifications and misfolding [13,14], it is difficult to determine the level of oxidative stress and inflammation in body fluids and link these to disease development.…”