Neuronal localization of sterol regulatory element binding protein-1 in the rodent and primate brain: a light and electron microscopic immunocytochemical study

Sterol regulatory element binding proteins are membrane-bound transcription factors that activate expression of several genes controlling cellular cholesterol and fatty acid homeostasis. The present study aimed to investigate the in vivo expression of sterol regulatory element binding protein-1 in t...

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Published in:	Neuroscience Vol. 97; no. 1; pp. 143 - 153
Main Authors:	Ong, W.Y, Hu, C.Y, Soh, Y.P, Lim, T.M, Pentchev, P.G, Patel, S.C
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-04-2000 Elsevier
Subjects:	Anatomy Animals Biological and medical sciences Brain - metabolism Brain - ultrastructure CCAAT-Enhancer-Binding Proteins Central nervous system cholesterol DNA-Binding Proteins - metabolism fatty acids Female Fundamental and applied biological sciences. Psychology gene expression Hippocampus - metabolism Hippocampus - pathology Immunohistochemistry Macaca fascicularis Male Mice Mice, Inbred BALB C Microscopy, Electron neurons Neurons - metabolism Neurons - ultrastructure Niemann-Pick Diseases - metabolism Niemann-Pick Diseases - pathology Niemann–Pick type C disease Nuclear Proteins - metabolism Primates Rats Rats, Wistar Rodentia SREBP-1 Sterol Regulatory Element Binding Protein 1 Temporal Lobe - metabolism Temporal Lobe - ultrastructure Transcription Factors Vertebrates: nervous system and sense organs LDL, low density lipoprotein fatty acids SREBP-1 PVDF, poly(vinylidene difluoride) neurons PBS, phosphate-buffered saline bHLH-Zip, basic helix-loop-helix-leucine zipper NP-C, Niemann–Pick disease, type C HMG-CoA, 3-hydroxy-3methylglutaryl-Coenzyme A cholesterol Niemann–Pick type C disease SREBP, sterol regulatory element binding protein gene expression Rat Immunocytochemistry Rodentia Central nervous system Monkey Binding protein Vertebrata Mammalia Mouse Primates Transcription factor Localization Brain (vertebrata) Sterol
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Summary:	Sterol regulatory element binding proteins are membrane-bound transcription factors that activate expression of several genes controlling cellular cholesterol and fatty acid homeostasis. The present study aimed to investigate the in vivo expression of sterol regulatory element binding protein-1 in the normal rodent and primate brain, and in the brain in Niemann–Pick type C disease mice. These mutant animals have lysosomal cholesterol accumulation and progressive neurodegeneration caused by an inactivating mutation of the NPC1 gene whose protein product functions in vesicular lipid trafficking. Western blot analysis of rat hippocampal homogenates with an affinity purified rabbit polyclonal antibody directed against an internal epitope of sterol regulatory element binding protein-1 identified a major 68,000 mol. wt protein consistent with the amino-terminal, transcriptionally active fragment of sterol regulatory element binding proteins-1. Immunocytochemically, this antibody revealed dense sterol regulatory element binding protein-1 staining of nuclei and light staining of the cytoplasm of cells in the neocortex and hippocampus in the rat, mouse and monkey brain. By electron microscopy of immunogold-labeled brain sections, these densely labeled cells were found to be neurons. In contrast, normal glial cells had little or no sterol regulatory element binding protein-1 immunoreactivity even at a developmental stage (postnatal day 9) which coincides with active myelination in the rat brain. Also, in contrast to the normal mouse brain, Niemann–Pick type C mice showed reduced staining of cortical and hippocampal neuronal nuclei. Since sterol regulatory element binding protein-1 has been shown to be a transcriptional regulator of fatty acid synthesis in vivo, the current findings of a predominantly neuronal nuclear expression of the 68,000 mol. wt transcriptionally active fragment of sterol regulatory element binding protein-1 highlights the established role of phospholipid metabolites and other fatty-acid containing lipids in neuronal signal transduction and other neuronal functions. Reduced sterol regulatory element binding protein-1 expression in neurons in Niemann–Pick type C may reflect a deficiency in fatty acid synthesis that could contribute to the neuronal dysfunction in this disorder.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0306-4522 1873-7544
DOI:	10.1016/S0306-4522(00)00031-2