Investigation of Fibrillar Aggregates Formed by Pathogenic Pre-pro-vasopressin Mutants that Cause ADNDI
Küçük Resim Yok
Tarih
2025
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Endocrine Soc
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Context: 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.
Açıklama
Anahtar Kelimeler
aggregates, ADNDI, AVP-NPII, amyloid, neurodegenerative diseases
Kaynak
Journal of Clinical Endocrinology & Metabolism
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
110
Sayı
6
