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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.

SUBMITTER: Cater JH

PROVIDER: S-EPMC6442606 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Cater Jordan H JH Kumita Janet R JR Zeineddine Abdallah Rafaa R Zhao Guomao G Bernardo-Gancedo Ana A Henry Amanda A Winata Wendy W Chi Mengna M Grenyer Brin S F BSF Townsend Michelle L ML Ranson Marie M Buhimschi Catalin S CS Charnock-Jones D Stephen DS Dobson Christopher M CM Wilson Mark R MR Buhimschi Irina A IA Wyatt Amy R AR

Proceedings of the National Academy of Sciences of the United States of America 20190308 13

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 ...[more]

PMID: 30850528

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aβ can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aβ nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity.Significance statementWe report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-β (Aβ) favors the stabilization of highly toxic oligomers and inhibits the formation of Aβ fibrils. The nitrated Aβ oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Project description:The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that β-amyloid (Aβ) accumulation is a key element. It follows that clearing the brain of Aβ would be beneficial, which has not been the case. Therefore, Aβ is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor β-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with Aβ. Protein data bank (pdb) entries for klotho and Aβ were searched on the RCSB Protein Data Bank for β-KL and AD amyloid β-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the Aβ and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of Aβ. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of Aβ suggests that Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

Dataset Information

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

Publications

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

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