ArticleThe Journal of biological chemistry2008
Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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107 citing papers in PubMed, 171 citations in OpenAlex.
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- Optimization of systemic AAV9 gene therapy in Niemann-Pick disease, type C1 mice.Life science alliance · 2026Article
- Differential Trafficking Phenotypes of NPC1 Mutant Proteins Reveal Distinct Cholesterol Accumulation Profiles.Journal of inherited metabolic disease · 2026Article
- Discovery of Autophagy Modulators that Increase I1061T NPC1 Expression and Promote Cholesterol Efflux in Niemann-Pick Type C Patient-Derived Fibroblasts.ACS chemical biology · 2026Article
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- Generation and characterization of human iPSC-derivedbioRxiv : the preprint server for biology · 2026Article
- Membralin Assembles a MAN1B1-VCP Complex to Target Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- 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
- 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
- Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.JCI insight · 2024Article
- Endogenous Protein-Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex.Journal of proteome research · 2024Article
- CRISPR/Cas9 technology in the modeling of and evaluation of possible treatments for Niemann-Pick C.Molecular biology reports · 2024Review
- Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function.International journal of molecular sciences · 2024Article
- Alterations in Proteostasis Mechanisms in Niemann-Pick Type C Disease.International journal of molecular sciences · 2024Review
- ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine.The Journal of clinical investigation · 2023Article
- StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival.Journal of cell science · 2023Article
- Severe neurometabolic phenotype inFrontiers in molecular neuroscience · 2023Article
47 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Over 200 disease-causing mutations have been identified in the NPC1 gene. The most prevalent mutation, NPC1(I1061T), is predicted to lie within the cysteine-rich luminal domain and is associated with the classic juvenile-onset phenotype of Niemann-Pick type C disease. To gain insight into the molecular mechanism by which the NPC1(I1061T) mutation causes disease, we examined expression of the mutant protein in human fibroblasts homozygous for the NPC1(I1061T) mutation. Despite similar NPC1 mRNA levels between wild type and NPC1(I1061T) fibroblasts, NPC1 protein levels are decreased by 85% in NPC1(I1061T) cells. Metabolic labeling studies demonstrate that unlike wild type protein, which undergoes a glycosylation pattern shift from Endo H-sensitive to Endo H-resistant species, NPC1(I1061T) protein remains almost exclusively Endo H-sensitive and exhibits a reduced half-life (t((1/2)) 6.5 h) versus wild type Endo H-resistant species (t((1/2)) 42 h). Treatment with chemical chaperones, growth at permissive temperature, or inhibition of proteasomal degradation increases NPC1(I1061T) protein levels, indicating that the mutant protein is likely targeted for endoplasmic reticulum-associated degradation (ERAD) due to protein misfolding. Overexpression of NPC1(I1061T) in NPC1-deficient cells results in late endosomal localization of the mutant protein and complementation of the NPC mutant phenotype, likely due to a small proportion of the nascent NPC1(I1061T) protein that is able to fold correctly and escape the endoplasmic reticulum quality control checkpoints. Our findings provide the first description of an endoplasmic reticulum trafficking defect as a mechanism for human NPC disease, shedding light on the mechanism by which the NPC1(I1061T) mutation causes disease and suggesting novel approaches to treat NPC disease caused by the NPC1(I1061T) mutation.
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