A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Zhang, Xiaojuan; Pham, Kien; Li, Danmeng; Schutte, Ryan J.; Gonzálo, David; Zhang, Penghui; Oshins, Regina; Tan, Weihong; Brantly, Mark; Liu, Chen; Ostrov, David A.

doi:10.3390/cells8121586

Cited by 10 publications

(4 citation statements)

References 30 publications

(49 reference statements)

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“…Recent observations on small molecules predicted to bind Z AAT [117][118][119] or mutant fibrinogen at the interface of the aggregation sites, thus increasing degradation and inhibiting intracellular accumulation, appear to be promising and in line with the observations from the present study.…”

Section: Discussionsupporting

confidence: 89%

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Callea

Francalanci

Giovannoni

2021

IJMS

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Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).

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Section: Discussionsupporting

confidence: 89%

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Callea

Francalanci

Giovannoni

2021

IJMS

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“…This study has shown that the mutation Thr371Ile implies a very mild effect on the stability of the globular γ-module. We wonder whether this observation could serve to set up a suitable experimental model aimed to inhibit aggregation or enhance degradation by using small molecules in analogy with Z AAT [18]. Presently, the attempt to reduce the storage by activating the autophagy/proteasome systems has given controversial/unsatisfactory results [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism

Güven

Bellacchio

Sağ

et al. 2020

IJMS

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Particular fibrinogen g chain mutations occurring in the g-module induce changes that hamper g-g dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen g chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the g chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen g chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen g chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (DDG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other g-module mutations causing HHHS.

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“…In perspective, the body of cumulated knowledge should hopefully open the road to future strategies aimed to look for novel small molecules [ 68 ] capable of binding cleaved AAT or fibrinogen at the polymerized interface, to co-localize with AAT or fibrinogen gamma chain mutants, to inhibit intracellular accumulation and/or to increase their degradation.…”

Section: Discussionmentioning

confidence: 99%

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

Callea

Desmet

2021

IJMS

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The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.

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A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Cited by 10 publications

References 30 publications

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

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