RESUMEN
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 (Aß) 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 Aß or small soluble Aß 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 Aß, 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.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Preeclampsia/metabolismo , Proteínas Gestacionales/metabolismo , Deficiencias en la Proteostasis/metabolismo , Péptidos beta-Amiloides/ultraestructura , Femenino , Humanos , Microscopía Electrónica de Transmisión , Chaperonas Moleculares/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/ultraestructura , Embarazo , Proteínas Gestacionales/ultraestructura , Agregación Patológica de Proteínas/metabolismo , Pliegue de Proteína , Estabilidad ProteicaRESUMEN
Fibrinogen, a major constituent of blood plasma, is highly susceptible to reaction with biological oxidants. It has been proposed that fibrinogen plays a role in antioxidant defence, but oxidation of fibrinogen is also known to disrupt normal blood clotting and is implicated in the pathology of atherosclerosis. In the present study, we show that the biological oxidant hypochlorite promotes the formation of soluble high molecular weight fibrinogen assemblies ≥40 × 106 Da, that do not accumulate when fibrinogen is induced to aggregate by other stresses such as heating or hydroxyl-mediated damage in vitro. Hypochlorite-modified fibrinogen is stable at 37 °C as assessed by precipitation assays, and has reduced susceptibility to iron-induced (hydroxyl-mediated) precipitation compared to native fibrinogen. In contrast to hypochlorite-modified albumin, which is known to be immunostimulatory, hypochlorite-modified fibrinogen does not induce RAW 264.7 (macrophage-like) cells or EOC 13.31 (microglia-like) cells to produce reactive oxygen species or induce cell death. Furthermore, depletion of fibrinogen from human blood plasma increases the immunostimulatory property of blood plasma after it is supplemented with hypochlorite in situ. We propose that reaction of hypochlorite with fibrinogen in blood plasma potentially reduces the accumulation of other hypochlorite-modified species such as immunostimulatory hypochlorite-modified albumin. The latter represent a novel role for fibrinogen in blood plasma antioxidant defence.