NRIF is a Regulator of Neuronal Cholesterol Biosynthesis Genes

Department of Biochemistry, Vanderbilt University School of Medicine, 8124A MRB III, Nashville, TN 37232, USA.
Journal of Molecular Neuroscience (Impact Factor: 2.34). 09/2008; 38(2):152-8. DOI: 10.1007/s12031-008-9136-9
Source: PubMed


Cholesterol is a critical component of neuronal membranes, required for normal signal transduction. We showed previously that adult hippocampal neurons co-express high levels of cholesterogenic enzymes, and that their expression is under the control of the p75 neurotrophin receptor (p75NTR). Most of the cellular effects of p75NTR are mediated via interacting proteins, including neurotrophin receptor interacting factor (NRIF). In this study, we tested the hypothesis that p75NTR-dependent regulation of cholesterol and lipid biosynthesis genes is mediated by NRIF. We found that in vitro down regulation of NRIF expression decreased the mRNA for two main cholesterogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr; EC and 7-dehydrocholesterol reductase (Dhcr7; EC Further analyses revealed that NRIF-dependent and Dhcr7-dependent transcriptional changes show a high degree of overlap, and that NRIF reduction resulted in reduced expression of sterol-sensing domain protein SCAP, followed by a decrease in mRNA levels of SRE-motif containing genes (HMGCR, FASN, SREBP2, S1P, and SQS1). Finally, a reduction in cholesterol biosynthesis-related gene expression was also observed in hippocampal tissue of mice with NRIF deletion. Our combined in vitro and in vivo studies suggest that hippocampal neuronal cholesterol biosynthesis is regulated through the p75NTR interacting factor NRIF.

Download full-text


Available from: Karoly Mirnics
  • Source
    • "It is remarkable that the modulation of the lipid metabolism, and of genes of the cholesterol biosynthesis among these, is a specific signature for the proNGF treatment. Indeed, it has been shown that cholesterol biosynthesis is connected on one side to the p75NTR-mediated signalling and apoptosis [55]–[57], and on the other side to the progression of AD [58], [59]. Given the proposed role of proNGF in p75NTR-mediated apoptosis [8] and the unbalance of the proNGF/NGF ratio in AD [18], [27], [60], further analysis will be required to evaluate the importance of this pathway in the specific biological outcome of proNGF in cellular systems and in vivo. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The biological activities of NGF and of its precursor proNGF are quite distinct, due to different receptor binding profiles, but little is known about how proNGF regulates gene expression. Whether proNGF is a purely pro-apoptotic molecule and/or simply a "less potent NGF" is still a matter of debate. We performed experiments to address this question, by verifying whether a proNGF specific transcriptional signature, distinct from that of NGF, could be identified. To this aim, we studied gene expression regulation by proNGF and NGF in PC12 cells incubated for 1 and 4 hours with recombinant NGF and proNGF, in its wild-type or in a furin-cleavage resistant form. mRNA expression profiles were analyzed by whole genome microarrays at early time points, in order to identify specific profiles of NGF and proNGF. Clear differences between the mRNA profiles modulated by the three neurotrophin forms were identified. NGF and proNGF modulate remarkably distinct mRNA expression patterns, with the gene expression profile regulated by NGF being significantly more complex than that by proNGF, both in terms of the total number of differentially expressed mRNAs and of the gene families involved. Moreover, while the total number of genes modulated by NGF increases dramatically with time, that by proNGFs is unchanged or reduced. We identified a subset of regulated genes that could be ascribed to a "pure proNGF" signalling, distinct from the "pure NGF" one. We also conclude that the composition of mixed NGF and proNGF samples, when the two proteins coexist, influences the profile of gene expression. Based on this comparison of the gene expression profiles regulated by NGF and its proNGF precursor, we conclude that the two proteins activate largely distinct transcriptional programs and that the ratio of NGF to proNGF in vivo can profoundly influence the pattern of regulated mRNAs.
    Full-text · Article · Jun 2011 · PLoS ONE
  • Source
    • "Agpat5 was also found to be significantly up-regulated in expression profiles of human AD brains [37]. Interestingly, cholesterol biosynthesis genes are regulated by the p75 NTR [38] [39] and the identification of Agpat5 biomarker could be linked to a p75 NTR transcriptional signature, possibly through increased proNGF signaling, as suggested to occur in the AD11 model [10]. The Wdfy1 gene is involved in mitochondrial functions [29] and together with D14Ertd449 and Psen1 was found to be associated with alcohol preference in C57BL mice [40], suggesting an interaction between these genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification of early and stage-specific biomarkers for Alzheimer’s disease (AD) is critical, as the development of disease-modification therapies may depend on the discovery and validation of such markers. The identification of early reliable biomarkers depends on the development of new diagnostic algorithms to computationally exploit the information in large biological datasets. To identify potential biomarkers from mRNA expression profile data, we used the Logic Mining method for the unbiased analysis of a large microarray expression dataset from the anti-NGF AD11 transgenic mouse model.The gene expression profile of AD11 brain regions was investigated at different neurodegeneration stages by whole genome microarrays. A new implementation of the Logic Mining method was applied both to early (1–3 months) and late stage (6–15 months) expression data, coupled to standard statistical methods. A small number of “fingerprinting” formulas was isolated,encompassing mRNAs whose expression levels were able to discriminate between diseased and control mice.We selected three differential “signature” genes specific for the early stage (Nudt19, Arl16, Aph1b), five common to both groups (Slc15a2, Agpat5, Sox2ot, 2210015, D19Rik, Wdfy1), and seven specific for late stage (D14Ertd449, Tia1, Txnl4, 1810014B01Rik, Snhg3, Actl6a, Rnf25).We suggest these genes as potential biomarkers for the early and late stage of AD-like neurodegeneration in this model and conclude that Logic Mining is a powerful and reliable approach for large scale expression data analysis. Its application to large expression datasets from brain or peripheral human samples may facilitate the discovery of early and stage-specific AD biomarkers.
    Full-text · Article · Jun 2011 · Journal of Alzheimer's disease: JAD
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gypsy/Ty3 retrotransposons, a group of long terminal repeat retrotransposons related to vertebrate retroviruses, are found in the genome of many fungi, plants, and animals. Although multiple families of such retroelements are present in fish, active Gypsy/Ty3 retrotransposons have all been eliminated from the lineage leading to mammals at least 180 million years ago. However, over 50 cellular genes related to Gypsy/Ty3 retrotransposons have been identified in mammalian genomes, indicating recurrent "molecular domestication" of these elements by their host during evolution. Most retrotransposon-derived proteins are conserved in divergent mammalian species and show sequence similarity to Gag proteins, major structural proteins for retroelement particle formation. Among the proposed and demonstrated biological functions for gag-derived genes, placenta formation in the mouse requires two gag-derived genes from the same family. Some forms of epigenetic regulation of gag-related genes might derive from host genome defense mechanisms that repelled retrotransposon ancestors. Together, such observations support a major role for transposable elements as a source of new coding sequences allowing important genetic innovations during evolution.
    No preview · Article · Oct 2009 · Annals of the New York Academy of Sciences
Show more