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. 2013 Aug;163(2):320-6.
doi: 10.1016/j.jpeds.2013.03.077. Epub 2013 May 8.

Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype

Gary A Silverman  1 , Stephen C Pak, David H Perlmutter
Affiliations

Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype

Gary A Silverman et al. J Pediatr. 2013 Aug.
No abstract available

Keywords: AT; ATD; ATM; ATZ; Alpha-1-antitrypsin; Alpha-1-antitrypsin deficiency; CBZ; COPD; Carbamazepine; Chronic obstructive pulmonary disease; ER; Endoplasmic reticulum; FDA; Federal Drug Administration; Mutant alpha-1-antitrypsin Z; Normal (wild type) alpha-1-antitrypsin; PBA; Phenylbutyric acid; RNA interference; RNAi; SNP; Single nucleotide polymorphism.

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Conflict of interest statement

The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Hypothetical paradigm for mechanisms of protection and susceptibility to liver disease in ATD. A putative liver cell from the protected host is shown on the left and compared to the susceptible host on the right. Mutant ATZ accumulates in the ER in each case but in cells of the susceptible host there is a subtle block in either ER degradation pathways (lower left) or cellular protective responses (lower right), leading to more accumulation/proteotoxicity.
Figure 2
Figure 2
A C. elegans animal expressing a transgene driving expression of ATZ fused to GFP. (Top) Large aggregates of retained ATZ (green) within intestinal cells appear in this single plane confocal image. The wild-type protein is rapidly secreted into the pseudocoelomic space and only visible at very high integrations (not shown). The red region is a pharyngeal marker to mark the head region. (Bottom) DIC image of the same animal showing normal anatomy except for large vacuolated regions in the intestinal cells corresponding to the positions of the ATZ aggregates in the image above. Scale bar is 100 microns.
Figure 3
Figure 3
Cellular targets of novel therapies for ATD. A liver cell is depicted with the putative targets of potential therapeutic strategies including gene silencing strategies that would inhibit synthesis of ATZ, autophagy enhancer drugs that increase degradation of ATZ and drugs like PBA and SAHA that could possibly increase secretion of ATZ.
See this image and copyright information in PMC

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