Human Z α<sub>1</sub>‐antitrypsin accumulates intracellularly and stimulates lysosomal activity when synthesised in the <i>Xenopus</i> oocyte

Bathurst, Ian C.; Errington, D.M.; Foreman, Richard C.; Judah, J. D.; Carrell, R.W.

doi:10.1016/0014-5793(85)80798-5

Cited by 25 publications

(6 citation statements)

References 13 publications

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“…Studies using mRNA isolated from normal (MM) and deficient (ZZ) livers showed both messages were equivalent in stability and in their translation and subsequent glycosylation in cell-free systems (32)(33)(34). Injection ofthe normal M and variant Z RNA into a surrogate cell, the toad oocyte, confirmed that there was equivalent initial synthesis of the two polypeptides but showed that, whereas all the M protein was secreted, only a fraction ofthe Z antitrypsin was secreted, most ofthe Z product being blocked within the oocyte at the final (high mannose) stage of processing (35)(36)(37)(38). This accumulation of the abnormal antitrypsin was accompanied by a burst of lysosomal activity in the oocyte, indicating that the blockage of the Z antitrypsin was accompanied by increased proteolytic degradation (36).…”

Section: Molecular Pathology Ofthe S and Z Variantsmentioning

confidence: 99%

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

Carrell¹

1986

J. Clin. Invest.

261

138

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Introduction: a,-antitrypsin and the serpins The maintenance of health requires a balance between the defensive and offensive systems ofthe body. One such balance that is now just becoming understood at the molecular level is the one between the enzymes that break down protein and the antiproteases that act as their inhibitors. Of particular importance is the group of closely related enzymes, the serine proteases, which are responsible for triggering the inflammatory cascades of the plasma such as coagulation, kinin release, fibrinolysis, and complement activation. The triggering by these enzymes of the plasma cascades is controlled by an appropriately specialized group of plasma protease inhibitors, e.g., antithrombin, antiplasmin, and the first component ofcomplement (C1)' inhibitor.

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Section: Molecular Pathology Ofthe S and Z Variantsmentioning

confidence: 99%

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

Carrell¹

1986

J. Clin. Invest.

261

138

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“…Indeed, through the use of inhibitors capable of selectively, and independently, targeting the proteasomal or lysosomal pathways, it has been demonstrated in somatic systems that proteins bearing more extensive modifications are preferentially directed away from the proteasome and toward lysosomal degradation pathways whereupon they are recycled via the action of acidic lysosomal hydrolases [ 190 ]. This pathway has been demonstrated in Xenopus oocytes wherein lysosomal activity was stimulated upon intracellular accumulation of damaged proteins [ 191 ].…”

Section: Increased Vulnerability Of the Ageing Oocyte To Oxidativementioning

confidence: 99%

Molecular Mechanisms Responsible for Increased Vulnerability of the Ageing Oocyte to Oxidative Damage

Mihalas

Redgrove

McLaughlin

et al. 2017

Oxidative Medicine and Cellular Longevity

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In their midthirties, women experience a decline in fertility, coupled to a pronounced increase in the risk of aneuploidy, miscarriage, and birth defects. Although the aetiology of such pathologies are complex, a causative relationship between the age-related decline in oocyte quality and oxidative stress (OS) is now well established. What remains less certain are the molecular mechanisms governing the increased vulnerability of the aged oocyte to oxidative damage. In this review, we explore the reduced capacity of the ageing oocyte to mitigate macromolecular damage arising from oxidative insults and highlight the dramatic consequences for oocyte quality and female fertility. Indeed, while oocytes are typically endowed with a comprehensive suite of molecular mechanisms to moderate oxidative damage and thus ensure the fidelity of the germline, there is increasing recognition that the efficacy of such protective mechanisms undergoes an age-related decline. For instance, impaired reactive oxygen species metabolism, decreased DNA repair, reduced sensitivity of the spindle assembly checkpoint, and decreased capacity for protein repair and degradation collectively render the aged oocyte acutely vulnerable to OS and limits their capacity to recover from exposure to such insults. We also highlight the inadequacies of our current armoury of assisted reproductive technologies to combat age-related female infertility, emphasising the need for further research into mechanisms underpinning the functional deterioration of the ageing oocyte.

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“…In one report, accumulation of @,-AT Z in Xenupus oocytes was associated with an increase in release of lysosomal enzymes. 90 Several recent studies in model systems have provided interesting and, perhaps, relevant information. Raposo er al.…”

Section: Mechanism Of Liver Cell Injurymentioning

confidence: 99%

REVIEW: α₁‐Antitrypsin deficiency associated liver disease

Teckman

Perlmutter

1997

J of Gastro and Hepatol

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alpha 1-Antitrypsin (alpha 1-AT) deficiency is the most common genetic cause of liver disease in children and genetic disease for which children undergo liver transplantation. It also causes cirrhosis and hepatocellular carcinoma in adults. Studies by Sveger in Sweden have shown that only a subgroup of the population with homozygous PiZZ alpha 1-AT deficiency develop clinically significant liver injury. Other studies have shown that the mutant alpha 1-AT Z molecule undergoes polymerization in the endoplasmic reticulum and that a subpopulation of alpha 1-AT-deficient individuals may be susceptible to liver injury because they also have a trait that reduces the efficiency by which the mutant alpha 1-AT Z molecule is degraded in the endoplasmic reticulum.

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Human Z α₁‐antitrypsin accumulates intracellularly and stimulates lysosomal activity when synthesised in the Xenopus oocyte

Cited by 25 publications

References 13 publications

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

Molecular Mechanisms Responsible for Increased Vulnerability of the Ageing Oocyte to Oxidative Damage

REVIEW: α₁‐Antitrypsin deficiency associated liver disease

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Human Z α1‐antitrypsin accumulates intracellularly and stimulates lysosomal activity when synthesised in the Xenopus oocyte

Cited by 25 publications

References 13 publications

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

Molecular Mechanisms Responsible for Increased Vulnerability of the Ageing Oocyte to Oxidative Damage

REVIEW: α1‐Antitrypsin deficiency associated liver disease

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Human Z α₁‐antitrypsin accumulates intracellularly and stimulates lysosomal activity when synthesised in the Xenopus oocyte

REVIEW: α₁‐Antitrypsin deficiency associated liver disease