ArticleThe Journal of biological chemistry2011
An "exacerbate-reverse" strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 89 citations in OpenAlex.
- Multi-omics reveal phosphatidic acid phosphatases modify Niemann-Pick type C disease severity.iScience · 2026Article
- Exploration of Bromodomain Proteins as Drug Targets for Niemann-Pick Type C Disease.International journal of molecular sciences · 2025Article
- The anti-cancer transition-state inhibitor MTDIA inhibits human MTAP, inducing autophagy in humanized yeast.Disease models & mechanisms · 2025Article
- Sterol O-Acyltransferase 1 (International journal of molecular sciences · 2024Article
- From beer to breadboards: yeast as a force for biological innovation.Genome biology · 2024Review
- Advances in research on potential therapeutic approaches for Niemann-Pick C1 disease.Frontiers in pharmacology · 2024Review
- Article
- Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.NPJ genomic medicine · 2023Review
- Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.Advances in experimental medicine and biology · 2023Article
- Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.International journal of molecular sciences · 2021Review
- Inherited disorders of lysosomal membrane transporters.Biochimica et biophysica acta. Biomembranes · 2020Review
- Understanding and Treating Niemann-Pick Type C Disease: Models Matter.International journal of molecular sciences · 2020Review
- Unbiased yeast screens identify cellular pathways affected in Niemann-Pick disease type C.Life science alliance · 2020Article
- Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity.Journal of lipid research · 2020Review
- Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid.The Journal of biological chemistry · 2020Article
- Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs.PloS one · 2020Article
- NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation.EMBO reports · 2019Article
- 2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2019Article
- Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann-Pick Disease Type C1.International journal of molecular sciences · 2019Review
- Glucocerebrosidase and its relevance to Parkinson disease.Molecular neurodegeneration · 2019Review
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1Δ strains grown under viable aerobic conditions. Deletion of components of the yeast NuA4 histone acetyltransferase complex in ncr1Δ strains conferred anaerobic inviability and accumulation of multiple sterol intermediates. Thus, we hypothesize an imbalance in histone acetylation in human NP-C disease. Accordingly, we show that the majority of the 11 histone deacetylase (HDAC) genes are transcriptionally up-regulated in three genetically distinct fibroblast lines derived from patients with NP-C disease. A clinically approved HDAC inhibitor (suberoylanilide hydroxamic acid) reverses the dysregulation of the majority of the HDAC genes. Consequently, three key cellular diagnostic criteria of NP-C disease are dramatically ameliorated as follows: lysosomal accumulation of both cholesterol and sphingolipids and defective esterification of LDL-derived cholesterol. These data suggest HDAC inhibition as a candidate therapy for NP-C disease. We conclude that pathways that exacerbate lethality in a model organism can be reversed in human cells as a novel therapeutic strategy. This "exacerbate-reverse" approach can potentially be utilized in any model organism for any disease.
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