Investigation of Fibrillar Aggregates Formed by Pathogenic Pre-pro-vasopressin Mutants that Cause ADNDI

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dc.contributor.authorVaizoglu, Refika Dilara
dc.contributor.authorErdem, Beril
dc.contributor.authorGul, Mehmet
dc.contributor.authorAcar, Ceren
dc.contributor.authorOzdemirel, Huseyin Ozgur
dc.contributor.authorOzer, Emel Saglar
dc.contributor.authorMergen, Hatice
dc.date.accessioned2026-04-04T13:33:05Z
dc.date.available2026-04-04T13:33:05Z
dc.date.issued2025
dc.departmentİnönü Üniversitesi
dc.description.abstractContext: Aggregations of unfolded or misfolded proteins, both inside and outside cells, are implicated in numerous diseases, collectively known as amyloidosis. Particularly, autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a rare disease caused by mutations in the AVPNPII gene, leading to the inability to secrete arginine vasopressin. These misfolded proteins accumulate within the endoplasmic reticulum (ER), causing cellular dysfunction. Objective: This study aimed to investigate the formation of amyloid-like aggregates within the cell resulting from misfolded mutant precursor proteins, which induce disulfide-linked oligomers due to the G45C, 207_209delGGC, G88V, C98X, C104F, E108D-1, E108D-2 and R122H mutations identified by our group in the AVP-NPII gene of ADNDI patients. Methods: Deglycosylation studies were performed to analyze the glycosylation patterns of mutant protein precursors. The involvement of these precursors in the ER-related degradation pathway was studied by conducting protease inhibition experiments. Disulfide-linked oligomer analysis determined the oligomerization status of the mutant precursors. Immunofluorescence and electron microscopy studies provided evidence of aggregate structures in the ER lumen. In vitro studies involved bacterial expression and fibril formation in Escherichia coli (E. coli). Results: Our findings demonstrated that the N-glycan structure of mutant precursors remains intact within the ER. Protease inhibition experiments indicated the involvement of these precursors in the ER-related degradation pathway. Disulfide-linked oligomer analysis revealed homo-oligomer structures in mutations. Immunofluorescence and electron microscopy studies confirmed the presence of aggregate structures in the ER lumen. In vitro studies showed that mutant precursors could form fibril structures in E. coli. Conclusion: Our study may support the idea that ADNDI belongs to the group of neurodegenerative diseases due to the formation of fibrillar amyloid aggregates in the cell.
dc.description.sponsorshipCouncil of Higher Education (CoHE)
dc.description.sponsorshipWe thank Prof. Dr. Martin Spiess and Nicole Beuret (University of Basel) for the gift of pLAVP, MYC his tag II plasmid, and C-terminal 6-His-tagged pET21b expression vector. This study was conducted as part of the doctoral dissertation titled Investigation of Amyloid-Like Aggregate Formations and Their Association with Autosomal Dominant Neurohypophyseal Diabetes Insipidus in Pro-vasopressin Mutants. R.D.V. is a PhD scholarship holder from the Council of Higher Education (CoHE) in the field of molecular pathology and laboratory medicine, which is one of the 100 national priority areas determined by CoHE within the scope of the 100/2000 program.
dc.identifier.doi10.1210/clinem/dgae749
dc.identifier.endpage1586
dc.identifier.issn0021-972X
dc.identifier.issn1945-7197
dc.identifier.issue6
dc.identifier.orcid0000-0002-8161-827X
dc.identifier.orcid0000-0002-3284-5185
dc.identifier.orcid0000-0003-4584-0954
dc.identifier.pmid39449655
dc.identifier.scopus2-s2.0-105005734259
dc.identifier.scopusqualityQ1
dc.identifier.startpage1577
dc.identifier.urihttps://doi.org/10.1210/clinem/dgae749
dc.identifier.urihttps://hdl.handle.net/11616/108905
dc.identifier.volume110
dc.identifier.wosWOS:001350114300001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherEndocrine Soc
dc.relation.ispartofJournal of Clinical Endocrinology & Metabolism
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20250329
dc.subjectaggregates
dc.subjectADNDI
dc.subjectAVP-NPII
dc.subjectamyloid
dc.subjectneurodegenerative diseases
dc.titleInvestigation of Fibrillar Aggregates Formed by Pathogenic Pre-pro-vasopressin Mutants that Cause ADNDI
dc.typeArticle

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