Biomedical subjects

Yong-Sun Kim

Publications and source records attributed to Yong-Sun Kim.

At least 37 records · Page 2Linked to original sources

PubMed2005

Polymorphisms at codons 56 and 174 of the prion-like protein gene (PRND) are not associated with sporadic Creutzfeldt-Jakob disease.

Association between sporadic Creutzfeldt-Jakob disease (CJD) and the prion-like protein gene (PRND) has been reported in the German population. To investigate whether the PRND polymorphisms are associated with an increased risk for developing sporadic CJD in the Korean population, we compared the genotype and allele frequencies of PRND polymorphisms in 110 sporadic CJD patients with those in 102 healthy Koreans. Two polymorphisms (P56L, T174 M) in Koreans were found in the open reading frame (ORF) of PRND. One heterozygote of P56L was observed in normal controls but not in sporadic CJD patients. A strong significant difference of PRND genotype frequency at codon 174 was found between the normal Korean population and various European populations. In contrast to results in the German population, our study did not show a significant difference in PRND genotype or allele frequency at codon 174 between sporadic CJD and normal controls. This was the first genetic association study of the ORF of PRND in an Asian CJD population.

Creutzfeldt-Jakob Syndrome↗

PubMed2005

A neuronal cell line that does not express either prion or doppel proteins.

Prions have been extensively studied since they represent a new class of infectious agents, the pathogenic prion protein (PrPSc). However, a central question on the physiological function of the normal prion protein (PrPC) remains unresolved. A cell model which was previously established from Rikn mice (PrP-/-) remains problematic because of its ectopic expression of the doppel (Dpl) which may have a neurotoxic effect. Here we established neuronal cell lines from Zürich I (PrP-/-) which do not express Dpl protein and ICR mice (PrP+/+) by transfecting with plasmid encoding for the large T antigen of SV40. The transformed cells have shown neuronal characteristics and, thus, these cell lines may provide a useful model to explore the function of neuronal PrPC.

Animals↗

PubMed2005

Expression of calsenilin in neurons and astrocytes in the Alzheimer's disease brain.

Calsenilin, a multifunctional Ca2+-binding protein, has been identified as an Alzheimer's disease-associated presenilin interactor. Here, we investigated the histochemical localization of calsenilin and its expression levels in the brains of sporadic Alzheimer's disease. Both messenger RNA and protein expression of calsenilin were observed in neurons of the cerebral cortex and hippocampus of control brains, and more intense staining was in Alzheimer's disease brains. Although calsenilin is primarily expressed in neurons, its immunoreactivity was also detected in reactive astrocytes of the Alzheimer's disease brains. In Alzheimer's disease brains, the caspase-derived fragment of calsenilin was only detected in cytosolic fraction. Our findings suggest that calsenilin overexpression in both neurons and reactive astrocytes may play an important role in apoptosis and in Alzheimer's disease pathology.

Aged↗

PubMed2005

Effect of transition metals (Mn, Cu, Fe) and deoxycholic acid (DA) on the conversion of PrPC to PrPres.

The PMCA (protein misfolding cyclic amplification) technique has been shown to drive the amplification of misfolded prion protein by PrP(Sc) seeds during several cycles of incubation-sonication. Here, we report that cyclic amplification of normal hamster brain homogenates treated with a number of transition metals (manganese [Mn], copper [Cu], and iron [Fe]) leads to conversion of PrP(C) into protease-resistant PrP(res). The efficiency of PrP(res) formation and the glycoforms induced by Mn were different from those obtained by Cu and Fe. Previous results have shown higher Mn and lower Cu levels in the affinity-purified PrP(Sc) from the brain of prion diseases compared with normal hamster brain homogenates. We focused on Mn because we observed higher levels of Mn in whole brain, mitochondria, and scrapie-associated fibril-enriched fractions from the brains of animals with prion disease. In the presence of minute quantities of Mn-induced PrP(res) template with a large amount of PrP(C), PrP(res) amplification is observed. A metal chelater, EDTA reverses the effect of Mn on PrP(res) amplification, suggesting that Mn may play a role in the formation of PrP(res). It has been proposed that metal-catalyzed oxidation of PrP leads to the oxidation of amino acids and extensive aggregation of oxidized PrP. Carboxyl acids such as deoxycholic acid (DA) are oxidized molecules produced by 3' oxidation pathway. In in vitro studies, the potent effect of Mn on PrP(res) amplification is augmented by DA in a dose-dependent manner. On the basis of the evidence of the elevated Mn levels in scrapie-associated fibril (SAF)-enriched preparations from the brains of animals with prion disease, Mn-loaded PrP and oxidized molecules such as carboxyl acids may contribute to the formation of the scrapie isoform of PrP in prion diseases.

Animals↗

PubMed2005

The expression of RANTES and chemokine receptors in the brains of scrapie-infected mice.

While chemokines play an important role in host defense, it has become abundantly clear that their expression is not solely restricted to immune cells. In this study, to investigate the role of chemokines in pathogenic mechanism of neurodegeneration in prion diseases, we determined the cerebral expression of RANTES, a major chemoattractant of monocytes and activated lymphocytes, and its receptors CCR1, CCR3 and CCR5 in ME7 scrapie-infected mice. The mRNA of RANTES gene was upregulated in the brains of scrapie-infected mice. Intense immunoreactivity of RANTES was observed only in glial fibrillary acidic protein (GFAP)-positive astrocytes of the hippocampus of the infected mice. In addition, the levels of mRNA expression of CCR1, CCR3, and CCR5 were increased in hippocampus of scrapie-infected brains compared to the values in controls. Immunostaining of CCR1, CCR3, and CCR5 was observed in reactive astrocytes of the hippocampal region of scrapie-infected brains. In addition, immunoreactivity of CCR5 was also observed in microglia of scrapie-infected brains. These results suggest that RANTES and its receptors may participate in amplifying proinflammatory responses and, thereby, exacerbate the neurodegeneration of prion diseases.

Animals↗

PubMed2005

Polymorphism at 3' UTR +28 of the prion-like protein gene is associated with sporadic Creutzfeldt-Jakob disease.

The downstream prion-like protein (doppel or Dpl) shares significant biochemical and structural homology with the cellular prion protein, PrP(C), which is considered as a responsible protein for the transmissible spongiform encephalopathies (TSEs) or prion diseases. Recently, polymorphisms in open reading frame (ORF) of the prion-like protein gene (PRND) have been analysed in relation to the occurrence of prion diseases and other neurodegenerative disorders. We examined the role of a single-nucleotide polymorphism (SNP) at 3' untranslated region (UTR) +28 of PRND. We analysed this polymorphism in 110 Korean patients with sporadic Creutzfeldt-Jakob disease (CJD) and 102 healthy control subjects. Significant differences in genotype (P=0.005) and allele (P=0.032) frequencies at 3' UTR +28 were observed between sporadic CJD and normal controls. This result suggests that the PRND polymorphism at 3' UTR +28 might be associated with the occurrence of sporadic CJD.

Aged↗

PubMed2005

Increased expression of phospholipase D1 in the brains of scrapie-infected mice.

Mitochondrial dysfunction and free radical-induced oxidative damage are critical factors in the pathogenesis of neurodegenerative diseases. Recently, phospholipid breakdown by phospholipase D (PLD) has been recognized as an important signalling pathway in the nervous system. Here, we examined the expression of PLD and alteration of membrane phospholipid in scrapie brain. We have found that protein expression and enzyme activity of PLD1 were increased in scrapie brains compared with controls; in particular, there was an increase in the mitochondrial fraction. PLD1 in mitochondrial membranes from scrapie brains, but not from control brains, was tyrosine phosphorylated. Furthermore, the concentration of mitochondrial phospholipids such as phosphatidylcholine and phosphatidylethanolamine was increased and the content of phosphatidic acid, a product of PLD activity, was up-regulated in the mitochondrial membrane fractions. Immunohistochemically, PLD1 immunoreactivity was significantly increased in activated astrocytes in both cerebral cortex and hippocampus of scrapie brains. Taken together, these results suggest that PLD activation might induce alterations in mitochondrial lipids and, in turn, mediate mitochondrial dysfunction in the brains of scrapie-infected mice.

Animals↗

PubMed2005

Polymorphisms of the prion protein gene (PRNP) in Hanwoo (Bos taurus coreanae) and Holstein cattle.

Polymorphisms in the prion protein gene (PRNP) in humans and sheep correlate with susceptibility to transmissible spongiform encephalopathies (TSEs). Bovine spongiform encephalopathy (BSE) has been reported in British and Japanese cattle; it has occurred thus far in Holstein cattle. BSE in Hanwoo (Bos taurus coreanae) cattle has not been diagnosed up to now. To characterize the bovine PRNP polymorphisms in Korean cattle, we analyzed the open reading frame (ORF) of PRNP in 120 Hanwoo (beef) cattle and 53 Holstein (dairy) cattle. Three polymorphisms were found, the third position of codon 78 (G-->A), the third position of codon 192 (C-->T), and the deletion of a single octa-repeat. An analysis of codon 78 revealed no difference in the genotype (P = 0.2026) or allele (P = 0.7180) frequencies between Hanwoo and Holstein animals. However, there were significant differences in the genotype (P < 0.0001) and allele (P < 0.0001) frequencies at PRNP codon 192 between Hanwoo and Holstein animals. The rate of Holstein animals with deletion of a single octa-repeat was 91.5% undeleted homozygotes, 8.5% heterozygotes (with R3 deletion), and 0% deleted homozygotes. However, none of the 120 Hanwoo animals had any octa-repeat deletions. The genotype (P < 0.0001) and allele (P < 0.0001) frequencies of a single octa-repeat-deletion were also significantly different between Hanwoo and Holstein animals.

Alleles↗

PubMed2004

Increased expression of the embryonic intermediate filament, nestin, in the brains of scrapie-infected mice.

This study investigated the immunohistochemical localization of nestin and its expression level in the brains of mice infected with scrapie, a disease which is characterized by spongiform neurodegeneration, neuronal vacuolation, and astrogliosis. Western blot analysis showed that the protein level of nestin was significantly increased in scrapie-infected brains compared with those of control brains. Nestin immunoreactivity in vascular endothelial cells was more intense in the brains of scrapie-infected mice compared with those of controls. There was marked nestin immunostaining in reactive astrocytes, but not in the neurons of the scrapie-infected brains. Considering all the findings, this study suggests that the nestin-positive cells, including glial cells and vascular endothelial cells, may have the potential to differentiate into mature glial cells and other neuronal elements, which would replenish lost neurons.

Animals↗

PubMed2004

Age-related changes of gamma-aminobutyric acid transaminase immunoreactivity in the hippocampus and dentate gyrus of the Mongolian gerbil.

We investigated the age-related changes of gamma-aminobutyric acid transaminase (GABA-T, a GABA degradation enzyme) in the hippocampus and dentate gyrus of the gerbil at postnatal month 1 (PM 1), PM 3, PM 6, PM 12, and PM 24. Age-related changes of GABA-T immunoreactivity were distinct in the hippocampal CA1 region and in the dentate gyrus. GABA-T immunoreactivity was weak at PM 1, but at PM 3, it had increased significantly, and then increased further. Between PM 6 and PM 12, strong GABA-T immunoreactivity was found in nonpyramidal cells (GABAergic) in the stratum pyramidale of the CA1 region, and at PM 6, strong GABA-T immunoreactivity was found in neurons of the dentate gyrus subgranular zone. At PM 24, CA1 pyramidal cells showed strong GABA-T immunoreactivity. Western blot analysis showed a pattern of GABA-T expression similar to that shown by immunohistochemistry at various ages. In conclusion, our results suggest that the age-related changes of GABA-T provide important information about the aged brain with GABA dysfunction.

4-Aminobutyrate Transaminase↗

PubMed2004

Identification of variants in cyclin D1 ( CCND1) and B-Cell CLL/lymphoma 2 ( BCL2).

CCND1 is an important cell-cycle regulatory protein associated with cell proliferation, poor prognosis and recurrence in cancer, while BCL2 is an important anti-apoptotic protein that plays a vital role in the regulation of the life span by controlling the rate of apoptosis. Recent studies have shown that CCND1 and BCL2 may be responsible for the body mass and the regulation of various metabolic processes. In an effort to discover additional polymorphism(s), we scrutinized the genetic polymorphisms in the CCND1 and BCL2. By direct DNA sequencing in 24 individuals, we identified 22 sequence variants within the 16 kb of whole CCND1 gene: one in exon 4, 17 in introns and four in the 3' UTR region. We also found eight sequence variants within 7.5 kb exon-intron boundaries of BCL2 gene: one in promoter, three in exon 1, and four in the 3' UTR region. Haplotypes, their frequencies and linkage disequilibrium coefficients (| D'| and r(2)), among polymorphisms were estimated. Among identified variants, seven and six variants of CCND1 and BCL2 were genotyped in a larger series of subjects ( n=320). Statistical analyses of CCND1 and BCL2 polymorphisms with two metabolic phenotypes revealed no significant association. The information concerning genetic polymorphisms of CCND1 and BCL2 might provide valuable information for future genetic studies of diseases.

5' Untranslated Regions↗

PubMed2004

Polymorphisms of the prion protein gene (PRNP) in a Korean population.

Human prion protein gene (PRNP) has been considered to be involved in the susceptibility of humans to prion diseases. Polymorphisms of methionine (Met)/valine (Val) at codon 129 and of glutamic acid (Glu)/lysine (Lys) at codon 219 are thought to play an important role in susceptibility to sporadic, iatrogenic and variant Creutzfeldt-Jakob disease (CJD). Although the genotype distribution of polymorphisms in PRNP open reading frame (ORF) has been reported in many European populations, among Asian groups, it has been reported only in the Japanese population. We examined the PRNP polymorphisms in 529 healthy Koreans. We observed that genotype frequencies at codon 129 was 94.33% Met/Met, 5.48% Met/Val, and 0.19% Val/Val with an allele frequency of 0.971:0.029 Met:Val, and that genotype frequencies at codon 219 was 92.06% Glu/Glu, 7.94% Glu/Lys, and 0% Lys/Lys with an allele frequency of 0.96:0.04 Glu:Lys. The frequencies of the Glu/Glu genotype ( chi(2)=10.075, P=0.0015) and of the Glu allele ( chi(2)=9.486, P=0.0021) at codon 219 were significantly higher in the Korean population than the Japanese population. In addition, the genotype frequency of heterozygotes (12.7%) at codons 129 or/and 219 was significantly lower in Koreans than in people from Great Britain ( chi(2)=89.52, P<0.0001). The deletion rate of one octarepeat (R2 deletion) was 0.38%, with 99.62% undeleted homozygotes and 0% deleted homozygote. To our knowledge, the R2 octarepeat deletion has never been found in people from countries other than Korea. The data of PRNP polymorphism at codon 219 suggest that Koreans may be more sensitive to sporadic CJD than the Japanese population.

Alleles↗

PubMed2004

The cellular prion protein (PrPC) prevents apoptotic neuronal cell death and mitochondrial dysfunction induced by serum deprivation.

Prion diseases are transmissible neurodegenerative disorders that are invariably fatal in humans and animals. Although the nature of the infectious agent and pathogenic mechanisms of prion diseases are not clear, it has been reported that prion diseases may be associated with aberrant metabolism of cellular prion protein (PrP(C)). In various reports, it has been postulated that PrP(C) may be involved in one or more of the following: neurotransmitter metabolism, cell adhesion, signal transduction, copper metabolism, antioxidant activity or programmed cell death. Despite suggestive results supporting each of these mechanisms, the physiological function(s) of PrP(C) is not known. To investigate whether PrP(C) can prevent apoptotic cell death in prion diseases, we established the cell lines stably expressing PrP(C) from PrP knockout (PrP(-/-)) neuronal cells and examined the role of PrP(C) under apoptosis and/or serum-deprived condition. We found that PrP(-/-) cells were vulnerable to apoptotic cell death and that this vulnerability was rescued by the expression of PrP(C). The expression levels of apoptosis-related proteins including p53, Bax, caspase-3, poly(ADP-ribose) polymerase (PARP) and cytochrome c were significantly increased in PrP(-/-) cells. In addition, Ca(2+) levels of mitochondria were increased, whereas mitochondrial membrane potentials were decreased in PrP(-/-) cells. These results strongly suggest that PrP(C) may play a central role as an effective anti-apoptotic protein through caspase-dependent apoptotic pathways in mitochondria, supporting the concept that disruption of PrP(C) and consequent reduction of anti-apoptotic capacity of PrP(C) may be one of the pathogenic mechanisms of prion diseases.

Animals↗

PubMed2004

Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies.

Transmissible spongiform encephalopathies (TSEs) are transmissible neurodegenerative diseases characterized by the accumulation of an abnormally folded prion protein, termed PrPSc, and the development of pathological features of astrogliosis, vacuolation, neuronal cell loss, and in some cases amyloid plaques. Although considerable structural characterization of prion protein has been reported, neither the method of conversion of cellular prion protein, PrPC, into the pathogenic isoform nor the post-translational modification processes involved is known. We report that in animal and human TSEs, one or more lysines at residues 23, 24, and 27 of PrPSc are covalently modified with advanced glycosylation end products (AGEs), which may be carboxymethyl-lysine (CML), one of the structural varieties of AGEs. The arginine residue at position 37 may also be modified with AGE, but not the arginine residue at position 25. This result suggests that nonenzymatic glycation is one of the post-translational modifications of PrP(Sc). Furthermore, immunostaining studies indicate that, at least in clinically affected hamsters, astrocytes are the first site of this glycation process.

Animals↗

PubMed2004

Genotyping of the JC virus in urine samples of healthy Korean individuals.

A human polyomavirus, JC virus (JCV) is ubiquitous in humans and infects children asymptomatically. It persists in renal tissue and is excreted progeny in urine. DNAs from urine samples of 100 healthy Korean individuals were screened for the presence of JCV by polymerase chain reaction (PCR). Twenty of the samples were positive for JCV. JCV DNA was found in one individual (4%) in the 1-19-year group, two individuals (9%) in the 20-39-year group, ten individuals (38%) in the 40-59-year group, seven individuals (28%) in the over 60-year group. The prevalence of JC viral DNA was the highest in the 40-59-year-old Korean population. To investigate genotypes of JCV in Korea, the genotypes were determined by DNA sequence analysis of the regulatory region (333 bp) and the VT-intergenic region (656 bp) of DNA from the 20 JCV isolates. We have identified three distinctive JCV strains in the regulatory region and ten distinctive JCV strains in the VT-intergenic region of DNA from the 20 isolates. Based on restriction fragment length polymorphism (RFLP) analysis and phylogenetic analysis of the VT-intergenic region of JCV, two distinct subtypes, CY and type 2A (MY), were found to be prevalent in this Korean population. CY and type 2A of JCV were identified in 13 individuals (65%) and four individuals (20%), respectively. Interestingly, type 1, which was distributed mostly in Europe, was found in 3 (15%) isolates from healthy Korean individuals.

Adolescent↗

PubMed2003

Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity.

Amyloid beta-peptide (Abeta), a causative molecule in the pathogenesis of Alzheimer's disease and the main component of senile plaques, is known to be neurotoxic in vitro and in vivo. The mechanisms involved in this Ab-mediated neurotoxicity are not fully understood, although there is evidence to suggest the involvement of oxidative stress, alterations in calcium homeostasis, and/or of CDK activators. Many studies have suggested that Ab may exert its toxic effect via the activation of transcription factors. Therefore, we investigated Ab- responsive genes in human neuroblastoma CHP134 cells using 3.1K human DNA microarrays. Among the several genes overexpressed or repressed by Ab, RTP801, Hi95/sestrin 2, and stanniocalcin 2 were confirmed to be Ab-mediated overexpression in the cells by semiquantitative RT-PCR. Transient expression of the sense RTP801 gene in CHP134 cells increased sensitivity to Abeta cytotoxicity and the expression of the antisense RTP801 gene protected the cells from the Abeta toxicity. These results suggest that RTP801 might play important roles in Abeta toxicity and the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗

PubMed2003

Phagocytosis of serum- and IgG-opsonized zymosan particles induces apoptosis through superoxide but not nitric oxide in macrophage J774A.1.

Phagocytosis of serum- and IgG-opsonized zymosan (SOZ and IOZ, respectively) particles into J774A.1 macrophages induced apoptosis of the cells, accompanied by the expression of p21(WAF1), one of cyclin-dependent protein kinase (CDK) inhibitors. Furthermore, phagocytosis of SOZ and IOZ particles into macophages induced superoxide formation. Tat-superoxide dismutase (SOD), which is readily transduced into the cells using Tat-domain, protected the cells from the apoptosis induced by phagocytosis of SOZ and IOZ particles. lipopolysaccharide (LPS) /interferon-gamma (IFN-gamma) also caused the apoptosis of the cells. However, Tat-SOD could not protect the cells from LPS/IFN-gamma induced apoptosis, suggesting that apoptosis mechanisms involved are different from each other. In the present study, we determined the amounts of nitric oxide (NO) produced by SOZ, IOZ, and LPS/IFN-gamma, and found that SOZ and IOZ did not induce the generation of NO in macrophages, whereas LPS/ IFN-gamma did. The apoptosis due to phagocytosis was accompanied with the release of cytochrome c from mitochondrial membrane to cytosolic fraction. Furthermore, SOZ and IOZ induced the cleavage of procasapase-3 (35 kDa) to give rise to an active caspase-3 (20 kDa), which was blocked by Tat- SOD but not by 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO), a scavenger of NO. On the other hand, LPS/IFN-gamma caused the activation of procaspase-3, which was blocked by PTIO but not by Tat-SOD. Taken together, phagocytosis of SOZ and IOZ particles induced apoptosis through superoxide but not NO in macrophages, accompanied with the release of cytochrome c and the activation of caspase-3.

Apoptosis↗

PubMed2002

Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress.

A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.

Aging↗