ArticlePloS one2014
Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 50 citations in OpenAlex.
- Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.Journal of inherited metabolic disease · 2026Review
- Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.EMBO molecular medicine · 2025Article
- Sestrin2 drives ER-phagy in response to protein misfolding.Developmental cell · 2024Article
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- 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
- Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1-imidazoline receptor.Aging cell · 2023Article
- A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.International journal of molecular sciences · 2022Review
- Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.PloS one · 2021Article
- Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis.International journal of molecular sciences · 2020Article
- Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways.International journal of molecular sciences · 2020Review
- Article
- How to Avoid a No-Deal ER Exit.Cells · 2019Review
- An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z.PloS one · 2019Article
- Mechanisms and therapeutic significance of autophagy modulation by antipsychotic drugs.Cell stress · 2018Review
- From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease.Molecular reproduction and development · 2017Review
- Review
- Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin.Hepatology (Baltimore, Md.) · 2017Article
- Autophagy in the liver: functions in health and disease.Nature reviews. Gastroenterology & hepatology · 2017Review
- Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2017Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
The classical form of α1-antitrypsin deficiency (ATD) is associated with hepatic fibrosis and hepatocellular carcinoma. It is caused by the proteotoxic effect of a mutant secretory protein that aberrantly accumulates in the endoplasmic reticulum of liver cells. Recently we developed a model of this deficiency in C. elegans and adapted it for high-content drug screening using an automated, image-based array scanning. Screening of the Library of Pharmacologically Active Compounds identified fluphenazine (Flu) among several other compounds as a drug which reduced intracellular accumulation of mutant α1-antitrypsin Z (ATZ). Because it is representative of the phenothiazine drug class that appears to have autophagy enhancer properties in addition to mood stabilizing activity, and can be relatively easily re-purposed, we further investigated its effects on mutant ATZ. The results indicate that Flu reverses the phenotypic effects of ATZ accumulation in the C. elegans model of ATD at doses which increase the number of autophagosomes in vivo. Furthermore, in nanomolar concentrations, Flu enhances the rate of intracellular degradation of ATZ and reduces the cellular ATZ load in mammalian cell line models. In the PiZ mouse model Flu reduces the accumulation of ATZ in the liver and mediates a decrease in hepatic fibrosis. These results show that Flu can reduce the proteotoxicity of ATZ accumulation in vivo and, because it has been used safely in humans, this drug can be moved rapidly into trials for liver disease due to ATD. The results also provide further validation for drug discovery using C. elegans models that can be adapted to high-content drug screening platforms and used together with mammalian cell line and animal models.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.