ArticleThe Journal of biological chemistry2010
Niemann-Pick C1 functions independently of Niemann-Pick C2 in the initial stage of retrograde transport of membrane-impermeable lysosomal cargo.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 65 citations in OpenAlex.
- All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2.Journal of immunology (Baltimore, Md. : 1950) · 2014Trial
- Kinetic modelling of sterol transport between plasma membrane and endo-lysosomes based on quantitative fluorescence and X-ray imaging data.Frontiers in cell and developmental biology · 2023Article
- Sphingolipid lysosomal storage diseases: from bench to bedside.Lipids in health and disease · 2021Review
- Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann-Pick disease type C.Cell death & disease · 2020Article
- Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid.eLife · 2019Article
- Lysosomal storage diseases.Nature reviews. Disease primers · 2018Review
- LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The Effects of Extracellular Serum Concentration on APP Processing in Npc1-Deficient APP-Overexpressing N2a Cells.Molecular neurobiology · 2018Article
- Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC.F1000Research · 2018Review
- The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease.Human molecular genetics · 2015Article
- Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport.The Journal of biological chemistry · 2015Article
- Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease.Human molecular genetics · 2015Article
- Complex lipid trafficking in Niemann-Pick disease type C.Journal of inherited metabolic disease · 2015Review
- Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin.Journal of lipid research · 2014Review
- Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.The Journal of clinical investigation · 2014Article
- Involvement of cathepsins B and L in inflammation and cholesterol trafficking protein NPC2 secretion in macrophages.Obesity (Silver Spring, Md.) · 2013Article
- Niemann-Pick Type C2 protein contributes to the transport of endosomal cholesterol to mitochondria without interacting with NPC1.Journal of lipid research · 2012Article
- The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction.The Journal of cell biology · 2012Review
- Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [(3)H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo.
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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.