Localization of Niemann–Pick C1 protein in astrocytes: Implications for neuronal degeneration in Niemann– Pick type C disease
Autor: | Edward B. Neufeld, Peter G. Pentchev, S Suresh, Ramesh C. Patel, Wei-Yi Ong, C. Y. Hu, Roscoe O. Brady, Yogesh C. Patel, Adele Cooney, E J Blanchette-Mackie, Shutish C. Patel, Ujendra Kumar |
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Rok vydání: | 1999 |
Předmět: |
Male
Mice Cricetinae hemic and lymphatic diseases Microscopy Immunoelectron Cells Cultured Neurons Niemann-Pick Diseases Membrane Glycoproteins Multidisciplinary Neurodegeneration Intracellular Signaling Peptides and Proteins Brain Biological Sciences Immunohistochemistry Recombinant Proteins medicine.anatomical_structure Neuroglia Female lipids (amino acids peptides and proteins) Niemann–Pick disease congenital hereditary and neonatal diseases and abnormalities Lipid storage disorder Molecular Sequence Data Immunocytochemistry CHO Cells Biology Transfection Antibodies Niemann-Pick C1 Protein medicine Animals Humans Amino Acid Sequence Infant Newborn Proteins nutritional and metabolic diseases Dendrites Fibroblasts Subcellular localization medicine.disease Molecular biology Axons Macaca fascicularis Membrane glycoproteins Astrocytes Nerve Degeneration biology.protein NPC1 Carrier Proteins |
Zdroj: | Proceedings of the National Academy of Sciences. 96:1657-1662 |
ISSN: | 1091-6490 0027-8424 |
Popis: | 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 NH 4 Cl. 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. |
Databáze: | OpenAIRE |
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