α1-Antitrypsin Deficiency

Perlmutter, David H.

doi:10.1007/978-1-4419-7107-4_46

Cited by 2 publications

(3 citation statements)

References 177 publications

(200 reference statements)

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“…The observation that only a subset of PiZZ individuals is more susceptible to liver injury has suggested that one or more additional inherited traits or environmental factors may play a role in potentiating the intracellular accumulation of the mutant protein or exaggerating the pathophysiological consequence of its accumulation .…”

Section: Discussionmentioning

confidence: 99%

“…The delay in degradation appears to be much slower in AAT PiZZ individuals with liver disease (susceptible host) as compared with those without liver disease. Proteasomal system, autophagy contributes to degradation of mutant protein in AAT deficiency . There is a lag in ER degradation of mutant protein in susceptible hosts.…”

Section: Discussionmentioning

confidence: 99%

“…The causes of the lag could be either insufficient autophagic response or proteasome‐dependent degradation. In addition to degradation, other adaptive mechanisms such as unfolded protein response, inhibition of translocation, ER overload pathway or stress have been implicated . The importance of autophagy and proteasome system in degradation of stored mutant fibrinogen has been demonstrated also in HFSD .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child

Sarı

Yılmaz

Gonul

et al. 2015

Liver International

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show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child

Sarı

Yılmaz

Gonul

et al. 2015

Liver International

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The Role of Autophagy in Alpha-1-Antitrypsin Deficiency: A Specific Cellular Response in Genetic Diseases Associated with Aggregation-Prone Proteins

Perlmutter¹

2006

Autophagy

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In the classical form of alpha-1-antitrypsin (AT) deficiency a point mutation renders aggregation-prone properties on a hepatic secretory protein. The mutant ATZ protein in retained in the endoplasmic reticulum (ER) of liver cells rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows the neutrophil proteases to slowly destroy the connective tissue matrix of the lung, resulting in premature development of pulmonary emphysema as early as the third decade of life. A gain-of-toxic function mechanism is responsible for liver inflammation and carcinogenesis. Indeed this deficiency is the most common genetic cause of liver disease in children in the US. It also causes chronic liver inflammation and carcinoma that manifests itself later in life. However, the majority of affected homozygotes apparently escape liver disease. This last observation has led to the concept that genetic and/or environmental modifiers affect the disposal of mutant ATZ within the ER or affect the protective cellular responses activated by accumulation of ATZ in the ER and, in turn, these modifiers determine which homozygotes develop liver inflammation and carcinoma. In this article I review a series of studies published over the last six years showing that autophagy is specifically activated by ER accumulation of ATZ and that it plays a critical role in the disposal of this mutant protein. Indeed, the most recent studies suggest that there is specialization of the autophagic pathway in that it is specifically activated by, and designed for disposal of, the aggregated forms of ATZ while the proteasome is specialized for disposal of soluble forms of ATZ. Together, these studies provide further evidence for the importance of autophagy in the cellular adaptive response to aggregated proteins in general.

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α1-Antitrypsin Deficiency

Cited by 2 publications

References 177 publications

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child

The Role of Autophagy in Alpha-1-Antitrypsin Deficiency: A Specific Cellular Response in Genetic Diseases Associated with Aggregation-Prone Proteins

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