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Deficient and null variants of SERPINA1 are proteotoxic in a Caenorhabditis elegans model of α1-antitrypsin deficiency

Cummings, EE and O'Reilly, LP and King, DE and Silverman, RM and Miedel, MT and Luke, CJ and Perlmutter, DH and Silverman, GA and Pak, SC (2015) Deficient and null variants of SERPINA1 are proteotoxic in a Caenorhabditis elegans model of α1-antitrypsin deficiency. PLoS ONE, 10 (10).

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α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregationprone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gainoffunction proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Cummings, EE
O'Reilly, LPloreilly@pitt.eduLOREILLY0000-0003-2597-0006
King, DE
Silverman, RM
Miedel, MT
Luke, CJcjl16@pitt.eduCJL16
Perlmutter, DHdhp6@pitt.eduDHP6
Silverman, GAgas12@pitt.eduGAS12
Pak, SCscp10@pitt.eduSCP10
ContributionContributors NameEmailPitt UsernameORCID
Date: 29 October 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0141542
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cell Biology and Molecular Physiology
School of Medicine > Pediatrics
Refereed: Yes
Date Deposited: 23 Aug 2016 14:44
Last Modified: 03 Apr 2021 15:55


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