Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0155339 (Brown)
12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A wealth of experimental evidence argues that infectious prions are composed largely, if not entirely, of the scrapie isoform of the prion protein. We attempted to restore scrapie infectivity after exposure to protein denaturants including urea, chaotropic salts, and SDS. None of the procedures restored infectivity. Dialysis to remove slowly chaotropic ions and urea failed to restore scrapie infectivity. Attempts to create monomers of the scrapie isoform of the prion protein under nondenaturing conditions using a wide variety of detergents have been unsuccessful, to date, except for one report claiming that scrapie infectivity could be recovered from 12% polyacrylamide gels after SDS/PAGE [Brown, P., Liberski, P. P., Wolff, A. & Gajdusek, D. C. (1990) Proc. Natl. Acad. Sci. USA 87, 7240-7244]. We found that < 0.001% of the infectious prion titer could be recovered from the region of a polyacrylamide gel where the denatured proteinase K-resistant core of the scrapie isoform of the prion protein and other 30-kDa proteins migrate. We conclude that under the denaturing conditions used for SDS/PAGE, the scrapie isoform of the prion protein is denatured and little or no renaturation occurs upon injection of fractions eluted from gels into animals for bioassays.
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PMID:Attempts to restore scrapie prion infectivity after exposure to protein denaturants. 846 92

Creutzfeldt-Jakob disease (CJD) is caused by an unusual prion protein. Rare CJD cases have been reported in Chinese individuals. This report describes the clinical manifestations of 14 Chinese individuals with clinically definite CJD from the National Taiwan University Hospital during the period 1976-1995. It is the largest case series of Chinese CJD up to now. All these patients fulfil the clinical definite diagnosis of CJD proposed by Brown et al. (1986), including rapidly evolving dementia, myoclonus, periodic electroencephalographic (EEG) activity (0.5-2 Hz) and death within 12 months. The clinical characteristics of the present series, including age at onset, sex ratio, duration, initial symptoms, neurological signs, EEG abnormalities, and neuroimaging studies were similar to those reported in other countries. However, there is a high incidence of initial ataxic gait as the presentation in our patients. Eight (57%) out of 14 patients initially had gait ataxia alone or in association with dementia. CJD should be considered in the differential provisional diagnosis of any middle-aged patient with a progressive ataxic syndrome.
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PMID:Is ataxic gait the predominant presenting manifestation of Creutzfeldt-Jakob disease? Experience of 14 Chinese cases from Taiwan. 886 27

A synthetic peptide consisting of amino acid residues 106 to 126 of the human prion protein (PrPc) that forms fibrils in vitro is toxic to cultured neurons. We have previously shown that the neurotoxic effect of this peptide is related to microglia activation (Brown et al., 1996a). For closer insight into this process of activation, we investigated the effect of the peptide on the intracellular free Ca2+ concentration ([Ca2+]i) in cultured microglia using Fura-2. Cultured microglia from wild-type as well as from PrPc gene-ablated mice (Prn-p0/0) responded to exposure to PrP106-126 with an increase in intracellular free calcium within 30 min. We observed two types of responses. Both in wild-type and Prn-p0/0 mice about half of the tested cells presented a small and often transient calcium increase after peptide application which was found to be independent of the extracellular calcium concentration. However, a further 33% of wild-type cells showed a strong and often permanent calcium increase depending on the extracellular calcium concentration, which was only rarely observed in Prn-p0/0 cells. To determine whether the response depended on the activation state of the microglia, we also examined LPS-treated activated microglia. The character of the calcium response remained unchanged, but significantly fewer cells responded. Our findings demonstrate the earliest reaction of microglia to a PrP fragment known to date.
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PMID:Increase of intracellular free Ca2+ in microglia activated by prion protein fragment. 933 39

Prion-related diseases are accompanied by neurodegeneration, astroglial proliferation and formation of proteinase K-resistant aggregates of the scrapie isoform of the prion protein (PrPSc). The synthetic PrP fragment 106-126 was reported to be neurotoxic towards cultured rat hippocampal neurons (Forloni, G., Angeretti, N., Chiesa, R., Monzani, E., Salmona, M., Bugiani, O. and Tagliavini, F. (1993) Nature 362, 543-546) and mouse cortical cells (Brown, D.R., Herms, J. and Kretzschmar, H.A. (1994) Neuroreport 5, 2057-2060). However, we found the viability of these and other neuronal cell types not to be impaired in the presence of PrP106-126 under widely varied sets of conditions. Aged preparations of the peptide as well as synthetic deamidated and isomerized derivatives that correspond to the aging products of the peptide proved also to lack neurotoxicity. Apparently, PrP106-126 cannot serve as a model for the interaction of PrP with neuronal cells.
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PMID:Neurotoxicity of prion peptide 106-126 not confirmed. 1064 43

Polymorphisms of the prion protein gene PRNP have been shown to influence the susceptibility/resistance to prion infections in human and sheep. In addition, the T174M polymorphism within the flanking prion doppel gene (PRND) was thought to be involved in susceptibility to sporadic Creutzfeldt-Jacob disease. To study a possible influence of DNA polymorphisms of the bovine PRND gene in bovine spongiform encephalopathy (BSE), previously identified and newly isolated DNA polymorphisms were genotyped in all available German cattle that tested positive for BSE. Genotypes and calculated haplotypes were compared with breeding bulls serving as controls. Analysis of the four major breeds Schwarzbunt (Holstein Friesian), Rotbunt (Holstein Red), Fleckvieh (Simmental), and Braunvieh (Swiss Brown) resulted in the isolation of the previously known polymorphisms R50H and R132Q and two novel synonymous single nucleotide polymorphisms (SNPs) C4820T and A5063T. Comparative genotype and haplotype analysis of BSE and control animals revealed a significantly different distribution of polymorphisms C4815T and R132Q in Fleckvieh animals but not in the other breeds tested. No association to BSE susceptibility was detectable for polymorphisms R50H and A5063T.
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PMID:DNA polymorphisms of the prion doppel gene region in four different German cattle breeds and cows tested positive for bovine spongiform encephalopathy. 1628 4

We present epidemiological data from Bavaria that indicates that animals of the Brown Swiss (BS) cattle breed might be more susceptible to BSE than animals from other breeds, both in terms of disease prevalence and length of the incubation period. BS animals were disproportionately represented among the BSE cases (BS represented about 9% of the susceptible population but 27% of actual cases). BS were slaughtered at a higher age (5.8 years vs. 5.0 years for other breeds), and there is a higher prevalence of feeding proprietary feeds to BS calves than calves from other breeds. There was no difference in the recorded feeding practice of BSE-positive animals from BS or other breeds. These results would lead to expect a higher prevalence of BSE in the BS population, with BS BSE animals being of equal age or older than BSE animals from other breeds. In contrast, median age at BSE detection was significantly lower in BS animals than in other breeds (61.4 vs. 68.8 months). There was no difference in the identification categories of BSE between BS animals and animals of other breeds that could explain this difference in age. BS cattle are reported to have more octapeptid repeats in the prion protein gene than other breeds, which could account for shorter incubation periods and higher susceptibility. These observations suggest that BS animals and their tissues should be used in further studies into genetic determinants of BSE susceptibility in cattle.
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PMID:Breed predisposition for BSE: epidemiological evidence in Bavarian cattle. 1673 97

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt-Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay was the most frequently positive investigation (88.1%) but performed significantly less well in the very uncommon MV2 and MM2 sub-types. Our findings confirm a number of determinants of principal investigation results in sporadic CJD and underscore the importance of recognizing these pre-test limitations before accepting the diagnosis excluded or confirmed. Combinations of investigations offer the best chance of detection, especially for the less common molecular sub-types such as MV2 and MM2.
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PMID:Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. 1692 53

The sporadic form of Creutzfeldt-Jakob disease (sCJD) has been classified on the basis of the molecular mass of the protease-resistant scrapie prion protein (PrP(Sc)), which can be type 1 or type 2, and the genotype at the methionine (M)/valine (V) polymorphic codon 129, which can be MM, MV or VV. In one classification proposed by Parchi et al., [Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I , Budka H , Kopp N , Piccardo P , Poser S , Rojiani A , Streichemberger N , Julien J , Vital C , Ghetti B , Gambetti P , Kretzschmar H . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-33.] the most common subtype of sCJD, designated sCJDMM1, is viewed as a single entity. Two other classifications proposed by Collinge et al. [Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 1996; 383: 685-90.] and Zanusso et al., [Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S . pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377-80.] respectively, subdivide sCJDMM1 into two subtypes on the basis of the different molecular mass and phenotypic characteristics, primarily disease duration. To resolve this discrepancy, we divided a group of 22 subjects with confirmed sCJDMM1 according to Parchi et al. into two sub-populations according to whether the disease duration was <5 months (short-duration subjects) or >7 months (long-duration subjects). We then examined the PrP(Sc) molecular mass under the conditions that allowed wide variability of the pH of the PrP(Sc) preparations as well as under stringent pH conditions, using high-resolution gel electrophoresis. We also compared the characteristics of the PrP(Sc) associated with the short- and long-duration subjects using two-dimensional immunoblot, conformational stability immunoassay and sucrose gradient fractionation. Finally, the two sub-populations were also compared with regard to their clinical and pathological features including the lesion profiles. When sample homogenization and protease digestion were performed under stringent pH conditions, the PrP(Sc) molecular mass did not differ between short- and long-duration sCJDMM1 subjects. The conformational characteristics of the protease-resistant PrP(Sc) as well as the clinical and pathological phenotypes were also homogeneous except for the more severe lesions of the long-duration cases. We therefore conclude that the variability of the PrP(Sc) molecular mass underlying the division of sCJDMM1 into two subtypes is largely due to pH variations during tissue preparation, and sCJDMM1 with short and long disease duration have similar phenotypes and PrP(Sc) characteristics. These data indicate that the differentiation of sCJDMM1 into two subgroups is not currently justified.
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PMID:Classification of sporadic Creutzfeldt-Jakob disease revisited. 1692 53

DNA from 252 bovine spongiform encephalopathy (BSE) cattle and 376 non-diseased control cattle were genotyped for nine loci in the prion protein (PRNP) gene region, three loci in the neurofibromin 1 (NF1) region and four control loci on different chromosomes. The allele and genotype frequencies of the control loci were similar in BSE and control cattle. In the analysed 7.4 Mb PRNP region, the largest differences between BSE and control cattle were found for the loci REG2, R16 and R18, which are located between +300 and +5600 bp, spanning PRNP introns 1 to 2. Carriers of the REG2 genotype 128/128 were younger at BSE diagnosis than those with the other genotypes (128/140 or 140/140). The predominant haplotype REG2 128 bp-R18 173 bp occurred more frequently (P < 0.001), and the second-most frequent haplotype (REG2 140 bp-R18 175 bp) occurred less frequently (P < 0.05) in BSE than in control cattle. The largest frequency differences between BSE and control groups were observed in the Brown Swiss breed. Across all breeds, most of the same alleles and haplotypes of the PRNP region were associated with BSE. In the 23-cM NF1 region, associations with BSE incidence were found for the RM222 allele and for the DIK4009 genotype frequencies. Cattle carrying RM222 genotypes with the 127- or 129-bp alleles were about half a year older at BSE incidence than those with other genotypes. Across the breeds, different alleles and genotypes of the NF1 region were associated with BSE. The informative DNA markers were used to localize the genetic disposition to BSE and may be useful for the identification of the causative DNA variants.
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PMID:Comparison of DNA variants in the PRNP and NF1 regions between bovine spongiform encephalopathy and control cattle. 1697 76

Prion diseases are thought to be caused by the misfolding of the ubiquitous neuronal membrane prion protein (PrP) through an unknown mechanism that may involve Cu(II) coordination to the PrP. Previous work has utilized Ni(II) as a diamagnetic probe for Cu(II) coordination [C.E. Jones, M. Klewpatinond, S.R. Abdelraheim, D.R. Brown, J.H. Viles, J. Mol. Biol. 346 (2005) 1393-1407]. Herein we investigate Ni(II) coordination to the PrP fragment PrP(93-114) (AcN-GGTHSQWNKPSKPKTNMKHMAG) at pH=10.0 by Ni K-edge X-ray absorption spectroscopy (XAS). We find that two equivalents of Ni(II) will coordinate to PrP(93-114) by UV/Vis titrations and mass spectrometry. Ni K-edge XAS data is consistent with Ni(II) ligated by five N/O based ligands (three N/O ligands at 2.01(2) Angstrom and two at 1.855(2) Angstrom). We were also able to locate a Ni-Ni vector at 3.1(1) Angstrom, which suggests the two Ni(II) centers are contained in a bis-mu-hydroxo dimer. We therefore suggest that Ni(II) may not be a suitable diamagnetic mimic for Cu(II) coordination within the PrP since differential coordination modes for the two metals exist.
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PMID:Ni K-edge XAS suggests that coordination of Ni(II) to the unstructured amyloidogenic region of the human prion protein produces a Ni(2) bis-mu-hydroxo dimer. 1712 7


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