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
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