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Nina F Schor

Publications and source records attributed to Nina F Schor.

15 recordsLinked to original sources
PubMed2006

Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain.

Normal brain function depends critically on cholesterol. Although cholesterol is synthesized locally in the adult brain, the precise anatomical localization of cholesterogenic enzymes is not known. Here we show that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAred) and 7-dehydrocholesterol reductase (7dhcred), the first and last enzymes, respectively, in the cholesterol biosynthesis pathway, are co-expressed in neurons throughout adult murine brain. Co-localization is most prominent in cortical, hippocampal, and cholinergic neurons. Since adult hippocampal and cholinergic neurons express p75 neurotrophin receptors (p75NTR) we hypothesized that p75NTR regulates expression of cholesterogenic enzymes. Treatment of Neuro2a neuroblastoma cells or primary cerebellar cultures with siRNA downregulates p75NTR and decreases the expression level of HMG-CoAred and 7dhcred. Native neuroblastoma cell lines with differential expression of p75NTR differentially express 7dhcred; 7dhcred expression correlates with p75NTR expression. This suggests that, in p75NTR-expressing cells, p75NTR regulates cholesterol synthesis through regulation of HMG-CoAred and 7dhcred expression. The unexpected localization of cholesterogenic enzymes in adult neurons suggests that at least some adult neurons retain the ability to synthesize cholesterol.

Acetylcholine↗
PubMed2006

p75NTR enhances PC12 cell tumor growth by a non-receptor mechanism involving downregulation of cyclin D2.

p75NTR is a member of the tumor necrosis superfamily of proteins which is variably associated with induction of apoptosis and proliferation. Cyclin D2 is one of the mediators of cellular progression through G1 phase of the cell cycle. The present study demonstrates the inverse relationship between expression of cyclin D2 and expression of p75NTR in PC12 cells. Induction of p75NTR expression in p75NTR-negative PC12 cells results in downregulation of cyclin D2; suppression of p75NTR expression with siRNA in native PC12 cells results in upregulation of cyclin D2. The effects of p75NTR on cyclin D2 expression are mimicked in p75NTR-negative cells by transfection with the intracellular domain of p75NTR. Cyclin-D2-positive PC12 cell cultures grow more slowly than cyclin-D2-negative cultures, and induction of expression of cyclin D2 slows the culture growth rate of cyclin-D2-negative cells. Finally, subcutaneous murine xenografts of cyclin-D2-negative, p75NTR-positive PC12 cells more frequently and more rapidly produce tumors than the analogous xenografts of cyclin-D2-positive, p75NTR-negative cells. These results suggest that p75NTR suppresses cyclin D2 expression in PC12 cells by a mechanism distinct from its function as a nerve growth factor receptor and that cyclin D2 expression decreases cell culture and xenografted tumor growth.

Animals↗
PubMed2006

Oxidation and cytotoxicity of 6-OHDA are mediated by reactive intermediates of COX-2 overexpressed in PC12 cells.

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, likely associated with dysregulation of oxidation of catechols, such as dopamine (DA) and 6-hydroxydopamine (6-OHDA), and resulting in oxidative stress. The involvement of cyclooxygenase-2 (COX-2) in pathogenesis of Parkinson's disease has been suggested. However, specific COX-2 triggered mechanisms participating in catalysis of DA oxidation and enhanced catechol-induced cytotoxicity remain poorly characterized. Here, we demonstrate that in a model biochemical system, recombinant heme-reconstituted COX-2 induced oxidation of 6-OHDA in the course of its peroxidase (H(2)O(2)-dependent) and cyclooxygenase (arachidonic acid (AA)-dependent) catalytic half-cycles. Similarly, COX-2 was able to stimulate 6-OHDA oxidation during its peroxidase- and cyclooxygenase half-cycles and caused oxidative stress in homogenates of PC12 cells stably overexpressing the enzyme (but not in mock-transfected cells). In addition, the increased levels of COX-2 were associated with enhanced cytotoxicity of 6-OHDA in stably transfected PC12 cells. Finally, co-oxidation of 6-OHDA by COX-2 triggered production of superoxide radicals critical for both propagation of 6-OHDA oxidation and induction of oxidative stress in COX-2 overexpressing cells. Thus, we conclude that both peroxidase and cyclooxygenase half-cycles of COX-2-catalyzed reactions are essential for COX-2-dependent activation of 6-OHDA oxidation, oxygen radical production, oxidative stress, and cytotoxicity.

Animals↗
PubMed2005

P75 neurotrophin receptor regulates expression of neural cell adhesion molecule 1.

Our recent transcriptome profiling studies suggest that presenilin 1 (PS1) regulates expression of neural cell adhesion molecule (Ncam1) through p75 neurotrophin receptor. To better understand regulation of Ncam1 transcript and protein levels by p75, we performed a series of in vitro and in vivo experiments. The combined results suggest that p75 receptor is required for both resting and NGF-induced Ncam1 expression. Activation of TrkA receptors alone does not upregulate Ncam1. The normal Ncam1 expression depends on the relative ratio of TrkA and p75 receptors, and p75 extracellular domain is necessary for baseline Ncam1 expression. NGF-induced Ncam1 expression is dependent on the presence of an intact palmitoylation site within p75 receptor. Finally, we show that the expression of Ncam1 is altered in brains of two transgenic mouse lines that express familial Alzheimer's disease (FAD)-linked PS1 variants, suggesting that expression of dominantly inherited mutant PS1 genes interferes with the normal Ncam1 expression via the p75 signaling pathway.

Alzheimer Disease↗
PubMed2005

Presenilin-1-dependent transcriptome changes.

Familial forms of Alzheimer's disease (FADs) are caused by the expression of mutant presenilin 1 (PS1) or presenilin 2. Using DNA microarrays, we explored the brain transcription profiles of mice with conditional knock-out of PS1 (cKO PS1) in the forebrain. In parallel, we performed a transcription profiling of the hippocampus and frontal cortex of the FAD-linked DeltaE9 mutant transgenic (TG) mice and matched controls [TG mice expressing wild-type human PS1 (hPS1)]. When the TG and cKO datasets were cross-compared, the majority of the 30 common expression alterations were in opposite direction, suggesting that the FAD-linked PS1 variant produces transcriptome changes primarily by gain of aberrant function. Our microarray studies also revealed an unanticipated inverse correlation of transcript levels between the brains of mice that coexpress DeltaE9 hPS1+ amyloid precursor protein (APP)695 Swe and DeltaE9 hPS1 single transgenic mice. The opposite directionality of these changes in transcript levels must be a function of APP and/or APP derivatives.

Alzheimer Disease↗
PubMed2005

The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress.

The low-affinity neurotrophin receptor, p75NTR, has been found to be pro- or anti-apoptotic depending upon the cell in which it is expressed. Reactive oxygen species play a major role in apoptosis induction and enactment. Using two polyclonal PC12 populations that, respectively, do or do not express p75NTR, this paper demonstrates that p75NTR expression confers resistance to oxidant stress upon PC12 cells maintained in serum-containing medium. The effect of p75NTR on cell survival is mimicked in p75-negative cells by expression of constructs that produce the p75NTR intracellular domain (ICD) or p75NTR with the extracellular domain deleted (DeltaECD), suggesting that binding of an extracellular ligand to p75NTR is not required. Our studies further document that the differential sensitivity to oxidant stress is serum-dependent and associated with differential oxidation of glutathione between p75-positive and p75-negative cells. These results suggest that the role of p75NTR in determining the consequences and treatment of age-related disorders and conditions in which reactive oxygen species are involved may require neither the extracellular receptor domain nor, by inference, the cognate extracellular ligands of this neurotrophin receptor.

Animals↗
PubMed2005

Transcriptome differences between the frontal cortex and hippocampus of wild-type and humanized presenilin-1 transgenic mice.

OBJECTIVE: The authors investigated the differences between the frontal cortical (Fc) and hippocampal (Hc) transcriptomes of wild type (wt mPS1), humanized presenilin-1 (PS1 [wt hPS1]) and Alzheimer-disease (AD)-linked DeltaE9 hPS1 mutant mice. METHODS: Using high-density oligonucleotide arrays, they recently performed transcriptome profiling of wt mPS1, wt hPS1, and DeltaE9 hPS1 mutant mice. Whereas these studies analyzed the commonalities of gene expression patterns and commonly-regulated genes across the two brain areas and across the animal models, the current study focused on the gene-expression differences across Fc and Hc, two critical AD-affected brain regions. RESULTS: The data revealed that in the wild-type mice, there are significant transcriptome differences between the Fc and the Hc tissue, and these expression differences are maintained in humanized transgenic mice carrying the wt hPS1 gene or DeltaE9 hPS1 mutation. Also, they provide evidence that a subset of genes show disturbed regional Fc-Hc gene-expression ratios in the transgenic mice carrying the DeltaE9 hPS1 mutation. Some of these genes, including stearoyl-Coenzyme A desaturase-2 (Scd2) and Prostaglandin D2 synthase (Ptgds), have been previously implicated in the pathology of AD. CONCLUSIONS: Data suggest that disturbed gene-expression ratios between cortical regions may be an important event in altered brain physiology.

Alzheimer Disease↗
PubMed2004

Prevention of catecholaminergic oxidative toxicity by 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl and its recycling complex with polynitroxylated albumin, TEMPOL/PNA.

Reactive oxygen species (ROS) generated from dopamine and its oxidation products have been implicated in the pathogenesis and toxicity from treatment of Parkinson's disease-associated autonomic neuropathy, and antioxidant therapies have been proposed as treatment and prophylaxis for this disorder. However, many antioxidants are rapidly and, under physiological conditions, irreversibly oxidized, rendering them redox-inactive. We have examined the potential of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl and polynitroxylated albumin (TEMPOL/PNA), an antioxidant complex that facilitates recycling of inactivated antioxidant to its redox-active form, as a protective agent against the toxicity of the catecholaminergic ROS generator, 6-hydroxydopamine (6-OHDA). TEMPOL/PNA is more effective against depression of activity level by 6-OHDA than the non-recycling antioxidant, TEMPOL, in a murine model of catecholaminergic oxidative damage. TEMPOL/PNA is also less toxic than TEMPOL in mice, allowing administration of higher doses of antioxidant. Both TEMPOL and TEMPOL/PNA give rise to prevention of apoptosis and to translocation of NF-kappaB from the cytoplasm to the nucleus of PC12 cells treated with 6-OHDA, but in vivo, TEMPOL/PNA maintains redox-active blood levels of TEMPOL for almost 5 h, whereas administration of TEMPOL alone results in clearance of blood redox activity within 1 h. PNA enhances the therapeutic index of TEMPOL, and the recycling antioxidant that results from their adjunctive administration may prove useful in disorders involving oxidative stress.

Albumins↗
PubMed2004

Effects of pH on the cytotoxicity of sodium trioxodinitrate (Angeli's salt).

Tumor tissues have an acidic microenvironment with a pH from 6.0 to 7.0, whereas the intra- and extracellular milieu of normal cells is 7.4. We have found that the hydrolysis of sodium trioxodinitrate (Angeli's salt; 1) to hydroxyl radical (*OH) was 10 times higher at pH = 6.0 than at pH = 7.4. It is hypothesized that the formation of *OH in solutions of 1 reflects the hydrolysis of the latter compound to nitroxyl (HNO) which dimerizes to cis-hyponitrous acid (HO-N=N-OH; 3) with concomitant azo-type homolytic fission to N(2) and *OH. In weakly acidified solutions, 1 exhibited strong toxicity to cancer cells that was inhibited by scavengers of hydroxyl radical, whereas no toxicity was observed at pH = 7.4. In a subcutaneous xenograft model of pheochromocytoma, 1 markedly inhibited tumor growth at a dose that was nontoxic to nude mice. These data suggest that the H(+)-amplified production of *OH from 1, and maybe other precursors of HNO, could be a selective mechanism for destruction cells with an acidic intra- or extracellular microenvironment.

Animals↗
PubMed2003

Formation of nitroxyl and hydroxyl radical in solutions of sodium trioxodinitrate: effects of pH and cytotoxicity.

Despite its negative redox potential, nitroxyl (HNO) can trigger reactions of oxidation. Mechanistically, these reactions were suggested to occur with the intermediate formation of either hydroxyl radical (.OH) or peroxynitrite (ONOO-). In this work, we present further experimental evidence that HNO can generate.OH. Sodium trioxodinitrate (Na2N2O3), a commonly used donor of HNO, oxidized phenol and Me2SO to benzene diols and.CH3, respectively. The oxidation of Me2SO was O2-independent, suggesting that this process reflected neither the intermediate formation of ONOO- nor a redox cycling of transition metal ions that could initiate Fenton-like reactions. In solutions of phenol, Na2N2O3 yielded benzene-1,2-diol and benzene-1,4-diol at a ratio of 2:1, which is consistent with the generation of free.OH. Ethanol and Me2SO, which are efficient scavengers of.OH, impeded the hydroxylation of phenol. A mechanism for the hydrolysis of Na2N2O3 is proposed that includes dimerization of HNO to cis-hyponitrous acid (HO-N=N-OH) with a concomitant azo-type homolytic fission of the latter to N2 and.OH. The HNO-dependent production of.OH was with 1 order of magnitude higher at pH 6.0 than at pH 7.4. Hence, we hypothesized that HNO can exert selective toxicity to cells subjected to acidosis. In support of this thesis, Na2N2O3 was markedly more toxic to human fibroblasts and SK-N-SH neuroblastoma cells at pH 6.2 than at pH 7.4. Scavengers of.OH impeded the cytotoxicity of Na2N2O3. These results suggest that the formation of HNO may be viewed as a toxicological event in tissues subjected to acidosis.

Antioxidants↗
PubMed2003

The supportive academic environment: ingredients for success.

Despite the many dire pronouncements of the moribund status of the academic triple threat, this species is far from extinct. Maintenance and, indeed, expansion of this pool of individuals requires their identification and support early in their careers, and nurturing and mentoring throughout their careers. Increasing demands for clinical service and revenue generation make it all the more critical that institutions and their faculty and administrative personnel in leadership positions support these increasingly rare academicians and that the individuals themselves develop and maintain diligence, superlative organizational skills, the ability to prioritize and the flexibility to reprioritize, perseverance, and above all, a sense of humor. Early in career development, perhaps the most important element in this equation is the mentor. The present article is in large measure a tribute to the mentoring role played by Dr. Michael J. Painter in the careers of his residents, fellows, and faculty throughout more than two decades as Chief of the Division of Child Neurology at the University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh.

Education, Medical↗
PubMed2003

Building a division of child neurology: a tribute to Michael J. Painter, MD.

In this era of changing priorities, regulations, and resources, it is useful to look both back and forward at the building of a division of child neurology in the context of the emergence of child neurology as a nationally and internationally recognized distinct subspecialty of both pediatrics and neurology. Both Pittsburgh and national colleagues of Dr Michael J. Painter were fortunate to have such a glimpse at a Festschrift held in his honor in January 2002 and, more recently, at the October 2002 meeting of Professors of Child Neurology, where he presented his view of "Building a Child Neurology Division the Old-Fashioned Way." The narrative that follows draws heavily from both of these events and from insights gained from Dr Painter's long and broad experience in the establishment and nurturing of both the specialty of child neurology and many of its current practitioners.

Child↗