ArticleHuman molecular genetics2018
High-content screen for modifiers of Niemann-Pick type C disease in patient cells.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 32 citations in OpenAlex.
- Multi-omics reveal phosphatidic acid phosphatases modify Niemann-Pick type C disease severity.iScience · 2026Article
- Molecular and histological characterizations reveal two distinct senescent microglia populations in Niemann-Pick disease type C mouse model.GeroScience · 2026Article
- Generation and characterization of human iPSC-derivedbioRxiv : the preprint server for biology · 2026Article
- Advances in mass spectrometry of lipids for the investigation of Niemann-pick type C disease.Lipids in health and disease · 2025Review
- Exploration of Bromodomain Proteins as Drug Targets for Niemann-Pick Type C Disease.International journal of molecular sciences · 2025Article
- Linking endo-lysosomal pH, sterol, and trafficking to neurodegenerative disease.FEMS yeast research · 2025Review
- Sterol O-Acyltransferase 1 (International journal of molecular sciences · 2024Article
- Development of quantitative high-throughput screening assays to identify, validate, and optimize small-molecule stabilizers of misfolded β-glucocerebrosidase with therapeutic potential for Gaucher disease and Parkinson's disease.bioRxiv : the preprint server for biology · 2024Article
- Advances in research on potential therapeutic approaches for Niemann-Pick C1 disease.Frontiers in pharmacology · 2024Review
- Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis.Oncogene · 2023Article
- Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation.iScience · 2023Article
- Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.Advances in experimental medicine and biology · 2023Article
- Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases.Reviews of physiology, biochemistry and pharmacology · 2023Article
- Article
- Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis.International journal of molecular sciences · 2021Article
- Reimagining dots and dashes: Visualizing structure and function of organelles for high-content imaging analysis.Cell chemical biology · 2021Review
- The rapidly evolving view of lysosomal storage diseases.EMBO molecular medicine · 2021Review
- Therapeutics Development for Alagille Syndrome.Frontiers in pharmacology · 2021Review
- Understanding and Treating Niemann-Pick Type C Disease: Models Matter.International journal of molecular sciences · 2020Review
- Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid.The Journal of biological chemistry · 2020Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Niemann-Pick type C (NPC) disease is a rare lysosomal storage disease caused primarily by mutations in NPC1. NPC1 encodes the lysosomal cholesterol transport protein NPC1. The most common NPC1 mutation is a missense mutation (NPC1I1061T) that causes misfolding and rapid degradation of mutant protein in the endoplasmic reticulum. Cholesterol accumulates in enlarged lysosomes as a result of decreased levels of lysosomal NPC1I1061T protein in patient cells. There is currently no cure or FDA-approved treatment for patients. We sought to identify novel compounds that decrease lysosomal cholesterol storage in NPC1I1061T/I1061T patient fibroblasts using a high-content screen with the cholesterol dye, filipin and the lysosomal marker, LAMP1. A total of 3532 compounds were screened, including 2013 FDA-approved drugs, 327 kinase inhibitors and 760 serum metabolites. Twenty-three hits were identified that decreased both filipin and LAMP1 signals. The majority of hits (16/21) were histone deacetylase (HDAC) inhibitors, a previously described class of modifiers of NPC cholesterol storage. Of the remaining hits, the antimicrobial compound, alexidine dihydrochloride had the most potent lysosomal cholesterol-reducing activity. Subsequent analyses showed that alexidine specifically increased levels of NPC1 transcript and mature protein in both control and NPC patient cells. Although unsuitable for systemic therapy, alexidine represents a unique tool compound for further NPC studies and as a potent inducer of NPC1. Together, these findings confirm the utility of high-content image-based compound screens of NPC1 patient cells and support extending the approach into larger compound collections.
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