ArticleProceedings of the National Academy of Sciences of the United States of America1999
Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 176 citations in OpenAlex.
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- In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy.Brain : a journal of neurology · 2022Article
- Treatment trials in Niemann-Pick type C disease.Metabolic brain disease · 2021Review
- Role of Lipid Transfer Proteins (LTPs) in the Viral Life Cycle.Frontiers in microbiology · 2021Review
- General Pathophysiology of Astroglia.Advances in experimental medicine and biology · 2019Review
- The role of Purkinje cell-derived VEGF in cerebellar astrogliosis in Niemann-Pick type C mice.BMB reports · 2018Article
- A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency.Scientific reports · 2017Article
- Astrocytes and lysosomal storage diseases.Neuroscience · 2016Review
- Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.Cell death & disease · 2016Article
- Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus.Journal of virology · 2015Article
- Cholesterol metabolism and homeostasis in the brain.Protein & cell · 2015Review
- Lysosomal Storage Diseases-Regulating Neurodegeneration.Journal of experimental neuroscience · 2015Review
- Genetic and laboratory diagnostic approach in Niemann Pick disease type C.Journal of neurology · 2014Review
- Current controversies in Niemann-Pick C1 disease: steroids or gangliosides; neurons or neurons and glia.Journal of applied genetics · 2013Review
- Olfactory deficits in Niemann-Pick type C1 (NPC1) disease.PloS one · 2013Article
- Article
- Astrocytes and disease: a neurodevelopmental perspective.Genes & development · 2012Review
- Characterization of the Niemann-Pick C pathway in alveolar type II cells and lamellar bodies of the lung.American journal of physiology. Lung cellular and molecular physiology · 2012Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Niemann-Pick type C disease (NP-C) is an inherited neurovisceral lipid storage disorder characterized by progressive neurodegeneration. Most cases of NP-C result from inactivating mutations of NPC1, a recently identified member of a family of genes encoding membrane-bound proteins containing putative sterol sensing domains. By using a specific antipeptide antibody to human NPC1, we have here investigated the cellular and subcellular localization and regulation of NPC1. By light and electron microscopic immunocytochemistry of monkey brain, NPC1 was expressed predominantly in perisynaptic astrocytic glial processes. At a subcellular level, NPC1 localized to vesicles with the morphological characteristics of lysosomes and to sites near the plasma membrane. Analysis of the temporal and spatial pattern of neurodegeneration in the NP-C mouse, a spontaneous mutant model of human NP-C, by amino-cupric-silver staining, showed that the terminal fields of axons and dendrites are the earliest sites of degeneration that occur well before the appearance of a neurological phenotype. Western blots of cultured human fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kDa protein. NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH4Cl. These studies show that NPC1 in brain is predominantly a glial protein present in astrocytic processes closely associated with nerve terminals, the earliest site of degeneration in NP-C. Given the vesicular localization of NPC1 and its proposed role in mediating retroendocytic trafficking of cholesterol and other lysosomal cargo, these results suggest that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration in NP-C.
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