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Journal articles on the topic 'Serpinopathie'

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Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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1

Faull, Sarah V., Emma L. K. Elliston, Bibek Gooptu, Alistair M. Jagger, Ibrahim Aldobiyan, Adam Redzej, Magd Badaoui, et al. "The structural basis for Z α1-antitrypsin polymerization in the liver." Science Advances 6, no. 43 (October 2020): eabc1370. http://dx.doi.org/10.1126/sciadv.abc1370.

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The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α1-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α1-antitrypsin as “polymer” chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α1-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α1-antitrypsin.

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2

Belorgey, Didier, Peter Hägglöf, Susanna Karlsson-Li, and David A. Lomas. "Protein Misfolding and the Serpinopathies." Prion 1, no. 1 (January 2007): 15–20. http://dx.doi.org/10.4161/pri.1.1.3974.

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3

Lomas, David A., and Robin W. Carrell. "Serpinopathies and the conformational dementias." Nature Reviews Genetics 3, no. 10 (October 2002): 759–68. http://dx.doi.org/10.1038/nrg907.

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4

DAVIES, M., and D. LOMAS. "The molecular aetiology of the serpinopathies." International Journal of Biochemistry & Cell Biology 40, no. 6-7 (June 2008): 1273–86. http://dx.doi.org/10.1016/j.biocel.2007.12.017.

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5

Lomas, D. A., D. Belorgey, M. Mallya, E. Miranda, K. J. Kinghorn, L. K. Sharp, R. L. Phillips, R. Page, A. S. Robertson, and D. C. Crowther. "Molecular mousetraps and the serpinopathies1." Biochemical Society Transactions 33, no. 2 (April 1, 2005): 321–30. http://dx.doi.org/10.1042/bst0330321.

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Members of the serine proteinase inhibitor or serpin superfamily inhibit their target proteinases by a remarkable conformational transition that involves the enzyme being translocated more than 70 Å (1 Å=10−10 m) from the upper to the lower pole of the inhibitor. This elegant mechanism is subverted by point mutations to form ordered polymers that are retained within the endoplasmic reticulum of secretory cells. The accumulation of polymers underlies the retention of mutants of α1-antitrypsin and neuroserpin within hepatocytes and neurons to cause cirrhosis and dementia respectively. The formation of polymers results in the failure to secrete mutants of other members of the serpin superfamily: antithrombin, C1 inhibitor and α1-antichymotrypsin, to cause a plasma deficiency that results in the clinical syndromes of thrombosis, angio-oedema and emphysema respectively. Understanding the common mechanism underlying the retention and deficiency of mutants of the serpins has allowed us to group these conditions as the serpinopathies. We review in this paper the molecular and structural basis of the serpinopathies and show how this has allowed the development of specific agents to block the polymerization that underlies disease.

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6

Miyata, Toshio, Reiko Inagi, Satoshi Sugiyama, and Nobuteru Usuda. "Serpinopathy and endoplasmic reticulum stress." Medical Molecular Morphology 38, no. 2 (June 10, 2005): 73–78. http://dx.doi.org/10.1007/s00795-004-0281-0.

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7

Ekeowa, Ugo I., Bibek Gooptu, Didier Belorgey, Peter Hägglöf, Susanna Karlsson-Li, Elena Miranda, Juan Pérez, et al. "α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies." Clinical Science 116, no. 12 (May 14, 2009): 837–50. http://dx.doi.org/10.1042/cs20080484.

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α1-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes α1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant α1-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (α1-antitrypsin and α1-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of α1-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.

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8

Ekeowa, U. I., J. Freeke, E. Miranda, B. Gooptu, M. F. Bush, J. Perez, J. Teckman, C. V. Robinson, and D. A. Lomas. "Defining the mechanism of polymerization in the serpinopathies." Proceedings of the National Academy of Sciences 107, no. 40 (September 20, 2010): 17146–51. http://dx.doi.org/10.1073/pnas.1004785107.

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9

Lomas, David A. "Molecular mousetraps, α1-antitrypsin deficiency and the serpinopathies." Clinical Medicine 5, no. 3 (May 1, 2005): 249–57. http://dx.doi.org/10.7861/clinmedicine.5-3-249.

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10

Gooptu, Bibek, and David A. Lomas. "Polymers and inflammation: disease mechanisms of the serpinopathies." Journal of Experimental Medicine 205, no. 7 (June 30, 2008): 1529–34. http://dx.doi.org/10.1084/jem.20072080.

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Members of the serpin (serine proteinase inhibitor) superfamily play a central role in the control of inflammatory, coagulation, and fibrinolytic cascades. Point mutations that cause abnormal conformational transitions in these proteins can trigger disease. Recent work has defined three pathways by which these conformers cause tissue damage. Here, we describe how these three mechanisms can be integrated into a new model of the pathogenesis of emphysema caused by mutations in the serpin α1-antitrypsin.

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11

Roussel, Benoit D., James A. Irving, Ugo I. Ekeowa, Didier Belorgey, Imran Haq, Adriana Ordóñez, Antonina J. Kruppa, et al. "Unravelling the twists and turns of the serpinopathies." FEBS Journal 278, no. 20 (June 20, 2011): 3859–67. http://dx.doi.org/10.1111/j.1742-4658.2011.08201.x.

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12

Lomas, David, A. "Polymerisation underlies alpha1-antitrypsin deficiency, dementia and other serpinopathies." Frontiers in Bioscience 9, no. 1-3 (2004): 2873. http://dx.doi.org/10.2741/1444.

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13

Crowther, Damian C., Didier Belorgey, Elena Miranda, Kerri J. Kinghorn, Lynda K. Sharp, and David A. Lomas. "Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies." European Journal of Human Genetics 12, no. 3 (December 24, 2003): 167–72. http://dx.doi.org/10.1038/sj.ejhg.5201127.

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14

Lomas, David A., and Ravi Mahadeva. "α1-Antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy." Journal of Clinical Investigation 110, no. 11 (December 1, 2002): 1585–90. http://dx.doi.org/10.1172/jci0216782.

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15

Lomas, D. A. "Parker B. Francis Lectureship. Antitrypsin Deficiency, the Serpinopathies, and Chronic Obstructive Pulmonary Disease." Proceedings of the American Thoracic Society 3, no. 6 (August 1, 2006): 499–501. http://dx.doi.org/10.1513/pats.200603-069ms.

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16

Galliciotti, Giovanna, and Elena Miranda. "Elucidating the pathological mechanisms of neurodegeneration in the lethal serpinopathy FENIB." Neural Regeneration Research 17, no. 8 (2022): 1733. http://dx.doi.org/10.4103/1673-5374.332142.

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17

Raccosta, Samuele, Fabio Librizzi, Alistair M. Jagger, Rosina Noto, Vincenzo Martorana, David A. Lomas, James A. Irving, and Mauro Manno. "Scaling Concepts in Serpin Polymer Physics." Materials 14, no. 10 (May 15, 2021): 2577. http://dx.doi.org/10.3390/ma14102577.

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α1-Antitrypsin is a protease inhibitor belonging to the serpin family. Serpin polymerisation is at the core of a class of genetic conformational diseases called serpinopathies. These polymers are known to be unbranched, flexible, and heterogeneous in size with a beads-on-a-string appearance viewed by negative stain electron microscopy. Here, we use atomic force microscopy and time-lapse dynamic light scattering to measure polymer size and shape for wild-type (M) and Glu342→Lys (Z) α1-antitrypsin, the most common variant that leads to severe pathological deficiency. Our data for small polymers deposited onto mica and in solution reveal a power law relation between the polymer size, namely the end-to-end distance or the hydrodynamic radius, and the polymer mass, proportional to the contour length. We use the scaling concepts of polymer physics to assess that α1-antitrypsin polymers are random linear chains with a low persistence length.

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18

Lomas, David A. "Genetic predisposition to chronic obstructive pulmonary disease: advances in α1-antitrypsin deficiency and the serpinopathies." Clinical Medicine 7, no. 5 (October 1, 2007): 446–47. http://dx.doi.org/10.7861/clinmedicine.7-5-446.

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19

Clarke, Lorne, L. A. Clarke, D. Randall, G. Sinclair, and K. Colobong. "4 Heparin cofactor II–thrombin complex as an MPS disease biomarker: Are the MPSs serpinopathies?" Molecular Genetics and Metabolism 92, no. 4 (December 2007): 12. http://dx.doi.org/10.1016/j.ymgme.2007.08.009.

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20

Inagi, Reiko, Masaomi Nangaku, Nobuteru Usuda, Akira Shimizu, Hiroshi Onogi, Yuko Izuhara, Kiyokazu Nakazato, et al. "Novel Serpinopathy in Rat Kidney and Pancreas Induced by Overexpression of Megsin." Journal of the American Society of Nephrology 16, no. 5 (March 23, 2005): 1339–49. http://dx.doi.org/10.1681/asn.2004070600.

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21

Sharp, Lynda K., Meera Mallya, Kerri J. Kinghorn, Zhen Wang, Damian C. Crowther, James A. Huntington, Didier Belorgey, and David A. Lomas. "Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis." FEBS Journal 273, no. 11 (April 25, 2006): 2450–552. http://dx.doi.org/10.1111/j.1742-4658.2006.05262.x.

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22

Broom, Helen R., Jessica A. O. Rumfeldt, and Elizabeth M. Meiering. "Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis." Essays in Biochemistry 56 (August 18, 2014): 149–65. http://dx.doi.org/10.1042/bse0560149.

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ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell–cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.

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23

Wilkinson, David J. "Serpins in cartilage and osteoarthritis: what do we know?" Biochemical Society Transactions 49, no. 2 (April 12, 2021): 1013–26. http://dx.doi.org/10.1042/bst20201231.

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Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders — collectively termed the ‘serpinopathies’ — but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by ‘omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues — as well as their dysregulation in OA — are explored.

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24

Motamedi-Shad, Neda, Alistair M. Jagger, Maximilian Liedtke, Sarah V. Faull, Arjun Scott Nanda, Enrico Salvadori, Joshua L. Wort, et al. "An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour." Biochemical Journal 473, no. 19 (September 27, 2016): 3269–90. http://dx.doi.org/10.1042/bcj20160159.

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Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A — on the opposite face of the molecule — more liable to adopt an ‘open’ state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin–enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the ‘open’ state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation.

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25

Malintan, Nancy T., Steven D. Buckingham, David A. Lomas, and David B. Sattelle. "Calcium signalling in mammalian cell lines expressing wild type and mutant human α1-Antitrypsin." Scientific Reports 9, no. 1 (November 21, 2019). http://dx.doi.org/10.1038/s41598-019-53535-1.

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AbstractA possible role for calcium signalling in the autosomal dominant form of dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), has been proposed, which may point towards a mechanism by which cells could sense and respond to the accumulation of mutant serpin polymers in the endoplasmic reticulum (ER). We therefore explored possible defects in Ca2+-signalling, which may contribute to the pathology associated with another serpinopathy, α1-antitrypsin (AAT) deficiency. Using CHO K1 cell lines stably expressing a wild type human AAT (MAAT) and a disease-causing polymer-forming variant (ZAAT) and the truncated variant (NHK AAT), we measured basal intracellular free Ca2+, its responses to thapsigargin (TG), an ER Ca2+-ATPase blocker, and store-operated Ca2+-entry (SOCE). Our fura2 based Ca2+ measurements detected no differences between these 3 parameters in cell lines expressing MAAT and cell lines expressing ZAAT and NHK AAT mutants. Thus, in our cell-based models of α1-antitrypsin (AAT) deficiency, unlike the case for FENIB, we were unable to detect defects in calcium signalling.

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26

Drouet, Christian, Alberto López-Lera, Arije Ghannam, Margarita López-Trascasa, Sven Cichon, Denise Ponard, Faidra Parsopoulou, et al. "SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE." Frontiers in Allergy 3 (March 31, 2022). http://dx.doi.org/10.3389/falgy.2022.835503.

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Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.

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