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Biomedical subjects

Charles J Epstein

Publications and source records attributed to Charles J Epstein.

At least 19 recordsLinked to original sources
PubMed2006

The challenge of Down syndrome.

Down syndrome (DS) has been recognized as a clinical entity for about 150 years, but it is only recently that there has been hope for the possibility to understand its pathogenesis and to use this information to devise approaches for the prevention and treatment of its numerous features. The earlier pessimism was due to several reasons, including: (i) the nature of the genetic defect that leads to the syndrome; (ii) the multiplicity of systems involved; and (iii) the high degree of variability of the phenotype. However, science has now caught up with the problem, and recent developments, especially in genetics, genomics, developmental biology and neuroscience, suggest that these potential impediments might not be as arduous as once appeared. As a result, basic research on DS is now rapidly accelerating, and there is hope that the findings will be translatable into benefit for people with DS.

Animals↗
PubMed2006

Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome.

Trisomy 21 or Down syndrome (DS) is the most common genetic birth defect associated with mental retardation. The over-expression of genes on chromosome 21, including SOD1 (Cu/Zn superoxide dismutase) and APP (amyloid-beta precursor protein) is believed to underlie the increased oxidative stress and neurodegeneration commonly described in DS. However, a segmental trisomy 16 mouse model for DS, Ts1Cje, has a subset of triplicated human chromosome 21 gene orthologs that exclude APP and SOD1. Here, we report that Ts1Cje brain shows decreases of mitochondrial membrane potential and ATP production, increases of reactive oxygen species, hyperphosphorylation of tau without NFT formation, increase of GSK3beta and JNK/SAPK activities and unaltered AbetaPP metabolism. Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS.

Adenosine Triphosphate↗
PubMed2006

Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.

Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.

Alzheimer Disease↗
PubMed2006

Effect of the reduction of superoxide dismutase 1 and 2 or treatment with alpha-tocopherol on tumorigenesis in Atm-deficient mice.

Atm-deficient mice, a cancer-prone model of the human disease ataxia-telangiectasia, display increased levels of oxidative stress and damage. Chronic treatment of these mice with the nitroxide antioxidant and superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) resulted in an increased latency to tumorigenesis. We initially hypothesized that the chemopreventative effect of Tempol was due to its SOD mimetic activity reducing cellular oxidative stress and damage. However, it is also possible that the chemopreventative effect of Tempol results from mechanisms other than directly reducing superoxide radical-induced oxidative stress and damage. To help distinguish between these possibilities, we attempted to genetically increase oxidative stress in Atm-deficient mice by either removing cytosolic Sod1 or reducing mitochondrial Sod2, or we attempted to decrease oxidative stress by treatment of Atm-deficient mice with alpha-tocopherol. Surprisingly, we found that reducing both Atm and Sod1 or Atm and Sod2 did not shorten latency to tumorigenesis or significantly affect life span. Furthermore, continuous administration of alpha-tocopherol did not affect latency to thymic lymphomas. Thus, genetically reducing Sod in Atm-deficient mice or treatment with alpha-tocopherol had no effect on survival or tumorigenesis, suggesting that the chemopreventative effect of Tempol may be at least partially independent of its effects on reducing oxidative damage and stress.

Animals↗
PubMed2006

Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase.

Sod2-/- mice, which are deficient in the mitochondrial form of superoxide dismutase (MnSOD), have a short survival time that is strongly affected by genetic background. This suggests the existence of genetic modifiers that are capable of modulating the degree of mitochondrial oxidative damage caused by the MnSOD deficiency, thereby altering longevity. To identify these modifier(s), we generated recombinant congenic mice with quantitative trait loci (QTL) containing the putative genetic modifiers on the short-lived C57BL/6J genetic background. MnSOD deficient C57BL/6J mice with a QTL from the distal region of chromosome 13 from DBA/2J were able to survive for as long as those generated on the long-lived DBA/2J background. Within this region, the gene encoding nicotinamide nucleotide transhydrogenase (Nnt) was found to be defective in C57BL/6J mice, and no mature NNT protein could be detected. The forward reaction of NNT, a nuclear-encoded mitochondrial inner membrane protein, couples the generation of NADPH to proton transport and provides NADPH for the regeneration of two important antioxidant compounds, glutathione and thioredoxin, in the mitochondria. This action of NNT could explain its putative protective role in MnSOD-deficient mice.

Alleles↗
PubMed2006

Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy.

We describe a novel phenotype in mice lacking the major antioxidant enzyme, CuZn-superoxide dismutase (Sod1(-/-) mice), namely a dramatic acceleration of age-related loss of skeletal muscle mass. Sod1(-/-) mice are 17 to 20% smaller and have a significantly lower muscle mass than wild-type mice as early as 3 to 4 months of age. Muscle mass in the Sod1(-/-) mice is further reduced with age and by 20 months, the hind-limb muscle mass in Sod1(-/-) mice is nearly 50% lower than in age-matched wild-type mice. Skeletal muscle tissue from young Sod1(-/-) mice has elevated oxidative damage to proteins, lipids, and DNA compared to muscle from young wild-type mice. The reduction in muscle mass and elevated oxidative damage are accompanied by a 40% decrease in voluntary wheel running by 6 months of age and decreased performance on the Rota-rod test at 13 months of age, but are not associated with a decline in overall spontaneous activity. In some of the old Sod1(-/-) mice, the loss in muscle mass is also associated with the presence of tremors and gait disturbances. Thus, the absence of CuZnSOD imposes elevated oxidative stress, loss of muscle mass, and physiological consequences that resemble an acceleration of normal age-related sarcopenia.

Aging↗
PubMed2006

Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster.

The generally accepted role of iron-regulatory protein 1 (IRP1) in orchestrating the fate of iron-regulated mRNAs depends on the interconversion of its cytosolic aconitase and RNA-binding forms through assembly/disassembly of its Fe-S cluster, without altering protein abundance. Here, we show that IRP1 protein abundance can be iron-regulated. Modulation of IRP1 abundance by iron did not require assembly of the Fe-S cluster, since a mutant with all cluster-ligating cysteines mutated to serine underwent iron-induced protein degradation. Phosphorylation of IRP1 at S138 favored the RNA-binding form and promoted iron-dependent degradation. However, phosphorylation at S138 was not required for degradation. Further, degradation of an S138 phosphomimetic mutant was not blocked by mutation of cluster-ligating cysteines. These findings were confirmed in mouse models with genetic defects in cytosolic Fe-S cluster assembly/disassembly. IRP1 RNA-binding activity was primarily regulated by IRP1 degradation in these animals. Our results reveal a mechanism for regulating IRP1 action relevant to the control of iron homeostasis during cell proliferation, inflammation, and in response to diseases altering cytosolic Fe-S cluster assembly or disassembly.

Animals↗
PubMed2006

Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging.

Mitochondrial function, hydrogen peroxide generation and oxidative damage were measured in hind-limb skeletal muscle from young (6-8 month) and old (27-29 month) wildtype and heterozygous Mn-superoxide dismutase (MnSOD) knockout mice (Sod2(+/-)). The reduction in MnSOD activity in the Sod2(+/-) mice makes these mice a good model to examine the implications of life-long elevated endogenous mitochondrial oxidative stress on mitochondrial function. ATP production was reduced approximately 30% with age in skeletal muscle mitochondria isolated from wildtype mice, and reduced 40-45% in mitochondria from both young and old Sod2(+/-) mice compared to the young wildtype mice. Release of hydrogen peroxide from skeletal muscle mitochondria increased 40-50% with age in both wildtype and Sod2(+/-) but was not higher in mitochondria from Sod2(+/-) mice. Activities of electron transport Complexes I and V were decreased 25-30% in both young and old Sod2(+/-) mice compared to wildtype mice, and were 25-30% lower in mitochondria from old wildtype and old Sod2(+/-) mice. DNA oxidative damage (oxo8dG levels) increased more than 45% with age and over 130% in the young Sod2(+/-) mice compared to the wildtype mice. These data show that mitochondrial oxidative stress in mouse skeletal muscle is increased with age, leading to alterations in mitochondrial function. In addition, increased oxidative stress generated by reduced activity of MnSOD does not exacerbate these alterations during aging.

Aging↗
PubMed2005

Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice.

To understand the role of oxidative stress and mitochondrial defects in the development of neurodegeneration, we examined the age-related pathological changes and corresponding gene expression profiles in homozygous mutant mice deficient in the mitochondrial form of superoxide dismutase (MnSOD, SOD2). These Sod2-/- mice, generated on a B6D2F1 background, developed ataxia at Postnatal Day (P) 11 and progressively deteriorated with frequent seizures by P14. Histopathological examination revealed neurodegenerative changes consistent with the neurological signs. Vacuolar degeneration was observed in neurons and neuropil throughout the brainstem and rostral cortex. The motor trigeminal nucleus in brainstem and the deeper layers of the motor cortex were the earliest regions to degenerate, with the thalamus and hippocampus affected at later stages. Oligonucleotide microarrays were used to compare gene expression profiles in the brainstem and thalamus of Sod2+/+ and -/- mice from birth to P18. Notably, a large set of heat-shock protein genes was transcriptionally down regulated, and this was most likely due to a reduction in the heat-shock transcription factor 1 (HSF1). Other major classes of differentially expressed genes include lipid biosynthesis and ROS metabolism.

Amino Acid Motifs↗
PubMed2005

A mechanism-based antioxidant approach for the reduction of skin carcinogenesis.

Studies in our laboratories showed that overexpression of manganese superoxide dismutase (MnSOD) reduced tumor incidence in a multistage skin carcinogenesis mouse model. However, reduction of MnSOD by heterozygous knockout of the MnSOD gene (MnSOD KO) did not lead to an increase in tumor incidence, because a reduction of MnSOD enhanced both cell proliferation and apoptosis. The present study extends our previous studies in the MnSOD KO mice and shows that apoptosis in mouse epidermis occurred prior to cell proliferation (6 versus 24 hours) when treated with tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). To investigate the possibility that a timed administration of SOD following apoptosis but before proliferation may lead to suppression of tumor incidence, we applied a SOD mimetic (MnTE-2-PyP(5+)) 12 hours after each TPA treatment. Biochemical studies showed that MnTE-2-PyP(5+) suppressed the level of protein carbonyls and reduced the activity of activator protein-1 and the level of proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Histologic examination confirmed that MnTE-2-PyP(5+) suppressed mitosis without interfering with apoptosis. Remarkably, the incidence and multiplicity of skin tumors were reduced in mice that received MnTE-2-PyP(5+) before cell proliferation. These results show a novel strategy for an antioxidant approach to cancer intervention.

Animals↗
PubMed2005

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life.

Mice deficient in CuZn superoxide dismutase (CuZnSOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1-/- mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1-/- and age-matched +/+ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1-/- mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.

Aging↗
PubMed2005

Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(171)65Dn and mouse chromosome 12.

The segmental trisomy model, Ts65Dn, has been a valuable resource for the study of the molecular and developmental processes associated with the pathogenesis of Down syndrome. However, male infertility and poor transmission of the small marker chromosome, T(17(16))65Dn, carrying the distal end of mouse Chromosome 16 (MMU16) are limiting factors in the efficient production of these animals for experimental purposes. We describe here the identification and preliminary characterization of mice, designated Ts[Rb(12.17(16))]2Cje, carrying a chromosomal rearrangement of the Ts65Dn genome whereby the marker chromosome has been translocated to Chromosome 12 (MMU12) forming a Robertsonian chromosome. This stable rearrangement confers fertility in males and increases the frequency of transmitted segmental trisomy through the female germline. We confirm retention of a dosage imbalance of human Chromosome 21 (HSA21)-homologous genes from App to the telomere and expression levels similar to Ts65Dn within the triplicated region. In addition, we characterized the dendritic morphology of granule cells in the fascia dentata in Ts[Rb(12.17(16))2Cje and 2N control mice. Quantitative confocal microscopy revealed decreased spine density on the dendrites of dentate granule cells and significantly enlarged dendritic spines affecting the entire population in Ts[Rb(12.17(16))]2Cje as compared to 2N controls. These findings document that the structural dendritic spine abnormalities are similar to those previously observed in Ts65Dn mice. We conclude that this new model of Down syndrome offers reproductive advantages without sacrificing the integrity of the Ts65Dn model.

Animals↗
PubMed2005

Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome.

Due to the homology between human chromosome 21 and mouse chromosome 16, trisomy 16 mice are considered animal models of Down syndrome (DS). Abnormal hippocampal synaptic plasticity and behavior have been reported in the segmental trisomy 16 Ts65Dn mouse. In the Ts1Cje DS mouse model, which has a shorter triplicated chromosomal segment than Ts65Dn, more subtle hippocampal behavioral deficits have been reported. In this study, we investigated CA1 hippocampal synaptic plasticity, long-term potentiation (LTP) and depression (LTD) in the Ts1Cje mouse. Field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 area of in vitro hippocampal slices from the Ts1Cje mouse and diploid controls, LTP was induced by a single tetanizing train pulse (1 s) at 100 Hz and LTD by a 900-pulse train at 1 Hz. We report for the first time that compared to diploid controls, the hippocampus from the Ts1Cje mouse had a smaller LTP and an increased LTD. The changes are less dramatic than had been reported previously for the Ts65Dn mouse. Furthermore, in the Ts1Cje mouse trains of pulses at both 20 Hz and 100 Hz produced a decrease in the evoked fEPSPs over the length of the train in comparison to diploid fEPSPs. These findings suggest that genes from Ts1Cje chromosome, including GIRK2 potassium channel, contribute to abnormal short- and long-term plasticity.

Action Potentials↗
PubMed2004

Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome.

The Ts65Dn mouse is a genetic model for Down syndrome. Although this mouse shows abnormalities in cognitive function that implicate hippocampus as well as marked deficits in hippocampal long-term potentiation, the structure of the hippocampus has been little studied. We characterized synaptic structure in Ts65Dn and control (2N) mice, studying the hippocampus (fascia dentata, CA1) as well as the motor and somatosensory cortex, entorhinal cortex, and medial septum. Confocal microscopy was used to examine immunostained presynaptic boutons and to detail the structure of dendrites after Lucifer yellow microinjection. Both presynaptic and postsynaptic elements were significantly enlarged in Ts65Dn in all regions examined. The changes were detected at the youngest age examined (postnatal day 21) and in adults. In studies detailing the changes in fascia dentata and motor cortex, the enlargement of spines affected the entire population, resulting in the presence of spines whose volume was greatly increased. Electron microscopy confirmed that boutons and spines were enlarged and demonstrated abnormalities in the internal membranes of both. In addition, spine density was decreased on the dendrites of dentate granule cells, and there was reorganization of inhibitory inputs, with a relative decrease in inputs to dendrite shafts and an increase in inputs to the necks of spines. Taken together, the findings document widespread abnormalities of synaptic structure that recapitulate important features seen in Down syndrome. They establish the Ts65Dn mouse as a model for abnormal synapse structure and function in Down syndrome and point to the importance of studies to elucidate the mechanisms responsible for synapse enlargement.

Animals↗
PubMed2004

A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties.

Superoxide, a potentially toxic by-product of cellular metabolism, may contribute to tissue injury in many types of human disease. Here we show that a tris-malonic acid derivative of the fullerene C60 molecule (C3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C3 and superoxide was not via stoichiometric "scavenging," as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism. A model is proposed in which electron-deficient regions on the C60 sphere work in concert with malonyl groups attached to C3 to electrostatically guide and stabilize superoxide, promoting dismutation. We also found that C3 treatment of Sod2(-/-) mice, which lack expression of mitochondrial manganese superoxide dismutase (MnSOD), increased their life span by 300%. These data, coupled with evidence that C3 localizes to mitochondria, suggest that C3 functionally replaces MnSOD, acting as a biologically effective SOD mimetic.

Animals↗
PubMed2004

Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome.

Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.

2-Amino-5-phosphonovalerate↗