ArticleHuman molecular genetics2014
A C. elegans model of human α1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 46 citations in OpenAlex.
- A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.Nature communications · 2026Article
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- Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.EMBO molecular medicine · 2025Article
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- ER-phagy drives age-onset remodeling of endoplasmic reticulum structure-function and lifespan.bioRxiv : the preprint server for biology · 2024Article
- A fluorescent reporter for rapid assessment of autophagic flux reveals unique autophagy signatures duringAutophagy reports · 2024Article
- A novel endoplasmic reticulum adaptation is critical for the long-lived Caenorhabditis elegans rpn-10 proteasomal mutant.Biochimica et biophysica acta. Gene regulatory mechanisms · 2023Article
- ER-associated RNA silencing promotes ER quality control.Nature cell biology · 2022Article
- Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z.Gastroenterology · 2022Article
- Plant and animal small RNA communications between cells and organisms.Nature reviews. Molecular cell biology · 2022Review
- The Autophagy Pathway: A Critical Route in the Disposal of Alpha 1-Antitrypsin Aggregates That Holds Many Mysteries.International journal of molecular sciences · 2021Review
- Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways.International journal of molecular sciences · 2020Review
- Article
- An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z.PloS one · 2019Article
- From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease.Molecular reproduction and development · 2017Review
- Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions.Current pathobiology reports · 2017Review
- α1-antitrypsin Deficiency: A Misfolded Secretory Protein Variant with Unique Effects on the Endoplasmic Reticulum.Endoplasmic reticulum stress in diseases · 2016Article
- Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy.The Journal of biological chemistry · 2015Article
- Movement of regulatory RNA between animal cells.Genesis (New York, N.Y. : 2000) · 2015Review
- The aggregation-prone intracellular serpin SRP-2 fails to transit the ER in Caenorhabditis elegans.Genetics · 2015Article
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
The accumulation of serpin oligomers and polymers within the endoplasmic reticulum (ER) causes cellular injury in patients with the classical form α1-antitrypsin deficiency (ATD). To better understand the cellular and molecular genetic aspects of this disorder, we generated transgenic C. elegans strains expressing either the wild-type (ATM) or Z mutant form (ATZ) of the human serpin fused to GFP. Animals secreted ATM, but retained polymerized ATZ within dilated ER cisternae. These latter animals also showed slow growth, smaller brood sizes and decreased longevity; phenotypes observed in ATD patients or transgenic mouse lines expressing ATZ. Similar to mammalian models, ATZ was disposed of by autophagy and ER-associated degradation pathways. Mutant strains defective in insulin signaling (daf-2) also showed a marked decrease in ATZ accumulation. Enhanced ATZ turnover was associated with the activity of two proteins central to systemic/exogenous (exo)-RNAi pathway: the dsRNA importer, SID-1 and the argonaute, RDE-1. Animals with enhanced exo-RNAi activity (rrf-3 mutant) phenocopied the insulin signaling mutants and also showed increased ATZ turnover. Taken together, these studies allude to the existence of a novel proteostasis pathway that mechanistically links misfolded protein turnover to components of the systemic RNAi machinery.
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