ArticleJIMD reports2012
Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking.
Article in JIMD reports, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 26 citations in OpenAlex.
- NPC1 trafficking via VPS41-dependent LAMP carriers regulates endosomal cholesterol homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Exploration of Bromodomain Proteins as Drug Targets for Niemann-Pick Type C Disease.International journal of molecular sciences · 2025Article
- Alterations in Proteostasis Mechanisms in Niemann-Pick Type C Disease.International journal of molecular sciences · 2024Review
- Challenges in the Definitive Diagnosis of Niemann-Pick Type C-Leaky Variants and Alternative Transcripts.Genes · 2023Review
- Saturation variant interpretation using CRISPR prime editing.Nature biotechnology · 2022Article
- Article
- Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism.International journal of molecular sciences · 2020Article
- Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18Journal of clinical medicine · 2020Article
- Modeling Niemann-Pick disease type C in a human haploid cell line allows for patient variant characterization and clinical interpretation.Genome research · 2019Article
- Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease.International journal of molecular sciences · 2016Article
- Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses.Science translational medicine · 2016Article
- Enzyme enhancers for the treatment of Fabry and Pompe disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Article
- Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities.Journal of lipid research · 2014Review
- Endoplasmic reticulum-associated degradation of Niemann-Pick C1: evidence for the role of heat shock proteins and identification of lysine residues that accept ubiquitin.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Niemann Pick type C (NPC) disease is an autosomal recessive disorder characterized by the lysosomal/late endosomal (LE) accumulation of unesterified cholesterol and other lipids due to a defect in the intracellular lipid trafficking. About 95% of patients present mutations in the NPC1 gene. Among the 290 mutations reported in the NPC1 gene, about 70% are missense. However, little information is available regarding the impact of missense mutations on NPC1 protein stability and function. In this study, we in vitro characterized the pathogenic effect of 7 NPC1 missense mutations. In all cases, the basal levels of mutant NPC1 expression were reduced with respect to wild type. Treatment of fibroblasts carrying NPC1 missense mutations in homo or hemizygosity, with the proteasome inhibitor MG132 or glycerol 10%, a chemical chaperone known to stabilize misfolded proteins, resulted in a significant increase of NPC1 protein levels in all cell lines, indicating that these mutants are subjected to proteasomal degradation due to protein misfolding The increment of NPC1 mutant protein induced by the proteasome inhibitor was associated with a localization of NPC1 protein within lysosomal/LE compartment. In cell lines carrying mutations p.N1156S, p.L1191F, p.V1165M, and p.I1061T, the increment of NPC1 mutant protein resulted in an improvement of the intracellular trafficking of cholesterol and GM1. These findings showed that it is possible to correct the NPC cellular phenotype by increasing the amount of endogenous NPC1 mutated protein, suggesting that at least some NPC1 mutations might be potentially rescued by small molecules-based chaperone therapy.
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Registered trials
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.