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 cho lesterol and fatty acid homeostasis. The present study aimed to investigate the in vivo expression of sterol regulatory element binding protein-1 in t he 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 th e NPC1 gene whose protein product functions in vesicular lipid trafficking. Western blot analysis of rat hippocampal homogenates with an affinity puri fied rabbit polyclonal antibody directed against an internal epitope of ste rol regulatory element binding protein-1 identified a major 68,000 mel. wt protein consistent with the amino-terminal, transcriptionally active fragme nt of sterol regulatory element binding proteins-1. Immunocytochemically, t his antibody revealed dense sterol regulatory element binding protein-1 sta ining of nuclei and light staining of the cytoplasm of cells in the neocort ex and hippocampus in the rat, mouse and monkey brain. By electron microsco py of immunogold-labeled brain sections, these densely labeled cells were f ound to be neurons. In contrast, normal glial cells had little or no sterol regulatory element binding protein-1 immunoreactivity even at a developmen tal 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 tr anscriptional regulator of fatty acid synthesis in vivo, the current findin gs of a predominantly neuronal nuclear expression of the 68,000 mel. wt tra nscriptionally active fragment of sterol regulatory element binding protein -1 highlights the established role of phospholipid metabolites and other fa tty-acid containing lipids in neuronal signal transduction and other neuron al functions. Reduced sterol regulatory element binding protein-1 expressio n in neurons in Niemann-Pick type C may reflect a deficiency in fatty acid synthesis that could contribute to the neuronal dysfunction in this disorde r. (C) 2000 IBRO. Published by Elsevier Science Ltd.