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Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 23678

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Prof. Dr. Francesco Callea

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Bugando Medical Centre, Department of Molecular Histopathology, Catholic University Health Allied Sciences, Mwanza, Tanzania
Interests: endoplasmic reticulum storage diseases; metabolic liver diseases; population genetics
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Special Issue Information

Dear Colleague,

This issue of IJMS is dealing with the main endoplasmic reticulum storage diseases (ERSD), Alpa-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS).

Molecular and genetic studies have unraveled the pathomorphogenesis of the basic disease process, i.e., plasma deficiency and accumulation in the hepatocyte ER of mutant proteins causing liver cell injury and progressive liver disease.

Mutations in AAT and Fibrinogen genes provoke conformational abnormalities and polymerization in the form of grotesque polypeptide arrays which result in fantastic molecular images of the 3D structure.

In addition, the discovery of AATD has disclosed the basic mechanism of pulmonary emphysema.

A few topics are devoted to therapeutic perspectives whose rationale is suggested by the detection of mutant ZAAT by serum IF as proof that ZAAT polymers can be exported to some extent, and by the demonstration of polymerized mutant proteins (either homo- or hetero-polymers) within the RER as an indication that the storage process is a very early event in protein synthesis.

Thus, small molecules are being selected and tested in vitro, in animal models, and in vivo for their capability of reducing the amount of storage, either by binding the cleaved ZAAT at the polymerization interphase to inhibit aggregation, or by enhancing its degradation.

Molecular research is expected to clarify a few features of HHHS: (a) only mutations in the gamma chain predispose to storage; (b) mutant gamma chains are not found in circulation; (c) hypo-fibrinogenemia does not result in overt extrahepatic clinical manifestations; (d) intrahepatic fibrinogen polymers can bind other molecules to form allopolymers.

Prof. Dr. Francesco Callea
Guest Editor

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Keywords

endoplasmic reticulum storage diseases
Alpa-1-antitrypsin deficiency
hereditary hypofibrinogenemia with hepatic storage
mutant proteins
fibrinogen
pathomorphogenesis

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Published Papers (6 papers)

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Research

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11 pages, 1203 KiB

Open AccessArticle

Boosted Pro-Inflammatory Activity in Human PBMCs by Lipopolysaccharide and SARS-CoV-2 Spike Protein Is Regulated by α-1 Antitrypsin

by Srinu Tumpara, Anna R. Gründing, Kokilavani Sivaraman, Sabine Wrenger, Beata Olejnicka, Tobias Welte, Maria J. Wurm, Paco Pino, Divor Kiseljak, Florian M. Wurm and Sabina Janciauskiene

Int. J. Mol. Sci. 2021, 22(15), 7941; https://doi.org/10.3390/ijms22157941 - 26 Jul 2021

Cited by 10 | Viewed by 4000

Abstract

For the treatment of severe COVID-19, supplementation with human plasma-purified α-1 antitrypsin (AAT) to patients is currently considered. AAT inhibits host proteases that facilitate viral entry and possesses broad anti-inflammatory and immunomodulatory activities. Researchers have demonstrated that an interaction between SARS-CoV-2 spike protein (S) and lipopolysaccharides (LPS) enhances pro-inflammatory responses in vitro and in vivo. Hence, we wanted to understand the potential anti-inflammatory activities of plasma-derived and recombinant AAT (recAAT) in a model of human total peripheral blood mononuclear cells (PBMCs) exposed to a combination of CHO expressed trimeric spike protein and LPS, ex vivo. We confirmed that cytokine production was enhanced in PBMCs within six hours when low levels of LPS were combined with purified spike proteins (“spike”). In the presence of 0.5 mg/mL recAAT, however, LPS/spike-induced TNF-α and IL-1β mRNA expression and protein release were significantly inhibited (by about 46–50%) relative to LPS/spike alone. Although without statistical significance, recAAT also reduced production of IL-6 and IL-8. Notably, under the same experimental conditions, the plasma-derived AAT preparation Respreeza (used in native and oxidized forms) did not show significant effects. Our findings imply that an early pro-inflammatory activation of human PBMCs is better controlled by the recombinant version of AAT than the human plasma-derived AAT used here. Considering the increasing clinical interest in AAT therapy as useful to ameliorate the hyper-inflammation seen during COVID-19 infection, different AAT preparations require careful evaluation. Full article

(This article belongs to the Special Issue Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease)

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18 pages, 3981 KiB

Open AccessArticle

The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant

by Riccardo Ronzoni, Ilaria Ferrarotti, Emanuela D’Acunto, Alice M. Balderacchi, Stefania Ottaviani, David A. Lomas, James A. Irving, Elena Miranda and Annamaria Fra

Int. J. Mol. Sci. 2021, 22(11), 5668; https://doi.org/10.3390/ijms22115668 - 26 May 2021

Cited by 9 | Viewed by 2939

Abstract

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure. Full article

(This article belongs to the Special Issue Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease)

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17 pages, 3397 KiB

Open AccessArticle

Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors

by Emanuele Bellacchio

Int. J. Mol. Sci. 2020, 21(23), 9016; https://doi.org/10.3390/ijms21239016 - 27 Nov 2020

Cited by 5 | Viewed by 4228

Abstract

Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparison of the molecular characteristics of the sites in fibrinogen γ-module, a fibrinogen component critical in multimerization processes, targeted by pathogenic variants (HGMD database) and by variants found in the healthy population (gnomAD database). The main result of this study is the identification of the molecular pathogenic mechanisms defining which pattern of disease inheritance is selected by mutations at the crossroad of autosomal recessive and negative dominant modalities. The observations in this analysis also warn about the possibility that several variants reported in the non-pathogenic gnomAD database might indeed be a hidden source of diseases with autosomal recessive inheritance or requiring a combination with other disease-causing mutations. Disease presentation might remain mostly unrevealed simply because the very low variant frequency rarely results in biallelic pathogenic mutations or the coupling with mutations in other genes contributing to the same disease. The results here presented provide hints for a deeper search of pathogenic mechanisms and modalities of disease inheritance for protein mutants participating in multimerization phenomena. Full article

(This article belongs to the Special Issue Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease)

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Review

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28 pages, 10466 KiB

Open AccessReview

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

by Francesco Callea, Paola Francalanci and Isabella Giovannoni

Int. J. Mol. Sci. 2021, 22(11), 5778; https://doi.org/10.3390/ijms22115778 - 28 May 2021

Cited by 6 | Viewed by 3232

Abstract

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). Full article

(This article belongs to the Special Issue Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease)

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14 pages, 5899 KiB

Open AccessReview

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

by Francesco Callea and Valeer Desmet

Int. J. Mol. Sci. 2021, 22(6), 2899; https://doi.org/10.3390/ijms22062899 - 12 Mar 2021

Cited by 8 | Viewed by 3907

Abstract

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. Full article

(This article belongs to the Special Issue Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease)

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17 pages, 1131 KiB

Open AccessReview

Hereditary Hypofibrinogenemia with Hepatic Storage

by Rosanna Asselta, Elvezia Maria Paraboschi and Stefano Duga

Int. J. Mol. Sci. 2020, 21(21), 7830; https://doi.org/10.3390/ijms21217830 - 22 Oct 2020

Cited by 27 | Viewed by 4356

Abstract

Fibrinogen is a 340-kDa plasma glycoprotein constituted by two sets of symmetrical trimers, each formed by the Aα, Bβ, and γ chains (respectively coded by the FGA, FGB, and FGG genes). Quantitative fibrinogen deficiencies (hypofibrinogenemia, afibrinogenemia) are rare congenital disorders characterized by low or unmeasurable plasma fibrinogen antigen levels. Their genetic basis is represented by mutations within the fibrinogen genes. To date, only eight mutations, all affecting a small region of the fibrinogen γ chain, have been reported to cause hereditary hypofibrinogenemia with hepatic storage (HHHS), a disorder characterized by protein aggregation in the endoplasmic reticulum, hypofibrinogenemia, and liver disease of variable severity. Here, we will briefly review the clinic characteristics of HHHS patients and the histological feature of their hepatic inclusions, and we will focus on the molecular genetic basis of this peculiar type of coagulopathy. Full article

(This article belongs to the Special Issue Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease)

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