title: Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia.
abstract: Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery, preeclampsia is the leading cause of iatrogenic preterm birth. We show that preeclampsia shares pathophysiologic features with recognized protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic dye Congo red), affinity for conformational state-dependent antibodies, and dysregulation of prototype proteolytic enzymes involved in amyloid precursor protein (APP) processing. Assessment of global protein misfolding load in pregnancy based on urine congophilia (Congo red dot test) carries diagnostic and prognostic potential for preeclampsia. We used conformational state-dependent antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with preeclampsia severity. In the first attempt to characterize the preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of ceruloplasmin, immunoglobulin free light chains, SERPINA1, albumin, interferon-inducible protein 6-16, and Alzheimer's β-amyloid. The human placenta abundantly expresses APP along with prototype APP-processing enzymes, of which the α-secretase ADAM10, the β-secretases BACE1 and BACE2, and the γ-secretase presenilin-1 were all up-regulated in preeclampsia. The presence of β-amyloid aggregates in placentas of women with preeclampsia and fetal growth restriction further supports the notion that this condition should join the growing list of protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for preeclampsia.
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. irina.buhimschi@nationwidechildrens.org.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Buhimschi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Unzila A
authors.initials: UA
authors.lastname: Nayeri
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA.
authors.forename: Guomao
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Lydia L
authors.initials: LL
authors.lastname: Shook
authors.affiliation: Center for Dementia Research, Nathan Kline Institute for Psychiatric Research and Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pensalfini
authors.affiliation: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Edmund F
authors.initials: EF
authors.lastname: Funai
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Bernstein
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92617, USA. Department of Biochemistry and Experimental Biochemistry Unit, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Catalin S
authors.initials: CS
authors.lastname: Buhimschi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure / Q000652:urine; D003224:Congo Red / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000378:metabolism / Q000473:pathology; D010920:Placenta / Q000201:enzymology; D011225:Pre-Eclampsia / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D011247:Pregnancy; D011379:Prognosis; D066329:Protein Aggregates; D017510:Protein Folding; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000939:Epitopes; D066329:Protein Aggregates; D012333:RNA, Messenger; D003224:Congo Red; D053829:Amyloid Precursor Protein Secretases