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- March 17, 2010
- 09:40 PM
- 435 views
Epidemiology of Human Prion Diseases in the U.S.
by Brian Appleby in CJD Blogger
In January 2010, members of the Centers for Disease Control and Prevention published an article in PLoS One regarding epidemiological data of human prion diseases in the United States. To those who have attended prion meetings in past couple of years, this is not new data as it has been presented before. The study examines the incidence of classical CJD and variant CJD (vCJD) within the U.S. between 1979-2008 and examines some basic demographic features of this population. The data were collected using a variety of different methods. From 1979-2006, data were collected from death certificates of U.S. residents and through alternative surveillance mechanisms from 1996-2008. These other surveillance efforts as of 6/1/2009 include collaboration with state health authorities and of directly reported or indirectly reported cases of possible vCJD. From 1999 onwards, text of death certificates were examined for CJD-related terms using SuperMICAR (Mortality Medical Indexing, Classification, and Retrieval system). The study uses the annual death rate to estimate the incidence of CJD (defined as the number of new cases per year) since the majority of cases have an illness duration of less than one year. From 1979-2006, the mean annual number of reported deaths secondary to CJD was 247 (range 172-304). The annual age-adjusted incidence of CJD was estimated at 0.97 per million individuals. In individuals older than 64 years of age, the incidence of CJD was estimated to be 4.8 per million individuals. The vast majority of deaths due to CJD were reported in whites (94.6%), resulting in an age-adjusted incidence for blacks of 0.4 per million individuals. Three deaths due to vCJD have been reported since 2004, all of which were determined to have acquired infection from outside of the U.S. In summary, this study estimates the incidence of CJD in the U.S. to be approximately 1 per million individuals, which is in accordance with data from other countries. The authors also describe a striking disparity between the incidence of CJD in whites and blacks. There are several limitations to this study, including but not limited to the various methods used for surveillance at different points in time and the reliance on reported data that may not have been uniformly reported across the country. Holman, R., Belay, E., Christensen, K., Maddox, R., Minino, A., Folkema, A., Haberling, D., Hammett, T., Kochanek, K., Sejvar, J., & Schonberger, L. (2010). Human Prion Diseases in the United States PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008521 del.icio.us Tags: Creutzfeldt-Jakob disease,CJD,vCJD,epidemiology,research... Read more »
Holman, R., Belay, E., Christensen, K., Maddox, R., Minino, A., Folkema, A., Haberling, D., Hammett, T., Kochanek, K., Sejvar, J.... (2010) Human Prion Diseases in the United States. PLoS ONE, 5(1). DOI: 10.1371/journal.pone.0008521
- March 8, 2010
- 10:08 AM
- 364 views
Brief Review of the P-CAPT Filter
by Brian Appleby in CJD Blogger
Following my last post regarding prion blood filtration, I was asked to cover the P-CAPT filter. Because leukoreduction only reduced prion infectivity by 72%, there is a need to develop other ways of eliminating prion infectivity in blood products. The P-CAPT Prion Capture Filter originated from a collaboration with Prometic, the American Red Cross, and several researchers. The majority of the initial research was performed by Luisa Gregori and colleagues in Bob Rohwer's lab, located at the Veterans Affairs Maryland Health Care System. In the absence of a blood-borne prion infectivity diagnostic test, preliminary work focused on depleting prions from blood using ligand resins. In one study, 6 ligands were chosen from a chemical library by Gregori and colleagues that were placed in columns subjected to a unit of leukoreduced human red blood cells (RBC's). Infectivity was assessed by comparing infectivity of hamster brain-derived scrapie spiked RBC's before and after their passage through the resin lined columns. Four ligands reduced infectivity titers by 3 to more than 4 log50 per mL. However, 0.01% infectivity could not be removed despite several column passages. Shortly thereafter, the same researchers reported a study that examined two specific resins', L13 and L13A, ability to remove prion infectivity in samples of scrapie-infected hamster whole blood following leukoreduction. None of the animals (n=96 and 100) that were inoculated with 500mL of the infected blood developed a transmissible spongiform encephalopathy (TSE) following a 540 day observation period. Another study was done that examined the application of two P-CAPT filters in series for the depletion of prion infectivity (slideshow below).The aforementioned studies demonstrate the P-CAPT filter's ability to successfully deplete prion infectivity from leukoreduced RBC's; however, these studies did not examine the practical application of the product. Several studies have investigated the pragmatic aspects of using the P-CAPT filter. One published report by Murphy and colleagues examined the P-CAPT filter's effect on RBC quality. They found that there was an approximate 9g of hemoblogin (Hb) lost per unit and in some cases, levels were below the standard specification of 40g. Moreover, hemolysis was increased, and prothrombin levels were reduced following filtration. The authors suggest that it may be safest to reduce the hemoglobin specification levels and transfuse more prion-filtered units instead of tranfusing potentially unsafe products. To examine this from another perspective, filtration of blood could require adults and children with hemoglobinopathies to be tranfused with an extra 4-5 and 1-2 units per year respectively. This would necessitate the collection of an additional 10,000-15,000 RBC units per year in England alone. Another study performed by Wiltshire and colleagues examined the filter's operational use, effects on blood quality, and for possible changes to blood group antigens. This study also detected a 7-8g loss of Hb and a reduction of hematocrit (Hct) of 6-9%. No changes in blood group antigens were noted. Filtration took an average of 60 minutes to complete and the filtration endpoint was difficult to assess leading to the possibility that filtration may be prematurely stopped, resulting in wasted RBC's that had not yet been filtered. Additionally, filter failure was estimated at 5.9%. However, the manufacturer was able to identify the possible cause of some of these failures leading to a modification of the outlet tube. A later study by the Scottish National Blood Transfusion Service of 125 units demonstrated no filter failures, an average filter time of 37.5 minutes, and a mean Hb loss of 6-7g. In summary, the P-CAPT filter has many benefits from a practicality standpoint in that it would likely require less personnel time and hence possible decrease the overall cost of its implementation. GregoriPrion2008FINAL p Capt Brochure Gregori, L., Lambert, B., Gurgel, P., Gheorghiu, L., Edwardson, P., Lathrop, J., MacAuley, C., Carbonell, R., Burton, S., Hammond, D., & Rohwer, R. (2006). Reduction of transmissible spongiform encephalopathy infectivity from human red blood cells with prion protein affinity ligands Transfusion, 46 (7), 1152-1161 DOI: 10.1111/j.1537-2995.2006.00865.xGregori L, Gurgel PV, Lathrop JT, Edwardson P, Lambert BC, Carbonell RG, Burton SJ, Hammond DJ, & Rohwer RG (2006). Reduction in infectivity of endogenous transmissible spongiform encephalopathies present in blood by adsorption to selective affinity resins. Lancet, 368 (9554), 2226-30 PMID: ... Read more »
Gregori, L., Lambert, B., Gurgel, P., Gheorghiu, L., Edwardson, P., Lathrop, J., MacAuley, C., Carbonell, R., Burton, S., Hammond, D.... (2006) Reduction of transmissible spongiform encephalopathy infectivity from human red blood cells with prion protein affinity ligands. Transfusion, 46(7), 1152-1161. DOI: 10.1111/j.1537-2995.2006.00865.x
Gregori L, Gurgel PV, Lathrop JT, Edwardson P, Lambert BC, Carbonell RG, Burton SJ, Hammond DJ, & Rohwer RG. (2006) Reduction in infectivity of endogenous transmissible spongiform encephalopathies present in blood by adsorption to selective affinity resins. Lancet, 368(9554), 2226-30. PMID: 17189034
Murphy CV, Eakins E, Fagan J, Croxon H, & Murphy WG. (2009) In vitro assessment of red-cell concentrates in SAG-M filtered through the MacoPharma P-CAPT prion-reduction filter. Transfusion medicine (Oxford, England), 19(3), 109-16. PMID: 19566667
Wiltshire, M., Thomas, S., Scott, J., Hicks, V., Haines, M., Cookson, P., Garwood, M., & Cardigan, R. (2009) Prion reduction of red blood cells: impact on component quality. Transfusion. DOI: 10.1111/j.1537-2995.2009.02500.x
- February 20, 2010
- 02:37 PM
- 421 views
Feasibility study of a plasma assay for variant CJD-Part 2
by Brian Appleby in CJD Blogger
This post will look at the study conducted by Guntz and colleagues. The authors examined the practical application of a plasma assay for the detection of variant Creutzfeldt-Jakob disease (vCJD) applied to all blood donations. The study intends to study three Blood Transfusion Establishments in France, where 60,000 blood samples will be analyzed over a period of 9-12 months. The current study only reports on the Strasbourg, Alsace site. The Amorfix EP-vCJD blood screening assay was examined. According to the manufacturer, the assay is able to detect 4 fg of recombinant prion protein per well and 1/1,000,000 dilution of vCJD brain homogenate, which is ten times more sensitive than what is minimally required by the UK Blood Transfusion Services. The assay concentrates prions, disrupts aggregates, and then uses a sensitive immunoassay to detect disaggregated PrP monomeric proteins. Instead of using proteinase K to differentiate PrPc from PrPres, the assay identifies prion protein aggregates. Initial testing resulted in a specificity of 97.6%. Repeat testing increased the specificity to 99.9% (20 positive samples). However, another retest of these samples resulted in no positive samples. Differences in retested reactive rates also suggested that samples should either be tested or frozen within 2 days of collection. One of the major practical problems of this test is that it is not automated. It requires manual pipetting and takes one technician 4 hours to do 160 samples. However, each Transfusion Center screens 700-1,000 blood samples per day! The test’s ability to detect endogenous prions has also not been demonstrated yet. Guntz P, Walter C, Schosseler P, Morel P, Coste J, & Cazenave JP (2010). Feasibility study of a screening assay that identifies the abnormal prion protein PrP(TSE) in plasma: initial results with 20,000 samples. Transfusion PMID: 20088835 Technorati Tags: prion,diagnostics,molecular biology,blood tranfusion,public health,CJD,vCJD ... Read more »
Guntz P, Walter C, Schosseler P, Morel P, Coste J, & Cazenave JP. (2010) Feasibility study of a screening assay that identifies the abnormal prion protein PrP(TSE) in plasma: initial results with 20,000 samples. Transfusion. PMID: 20088835
- January 28, 2010
- 11:31 AM
- 494 views
Presence of prion proteins in non-neuronal tissue in a case of variant CJD
by Brian Appleby in CJD Blogger
A recent article in the journal PLOS One describes a novel finding of abnormal prion proteins (PrPres) in additional non-neuronal tissues of a variant CJD (vCJD) patient. The study comes from the National Prion Disease Pathology Surveillance Center, located at Case Western University in Cleveland, Ohio. Prior to this study, there was evidence that PrPres was present in some non-neuronal tissues as shown below. The present study examined other tissues for the possible presence of PrPres. Tissue samples were obtained from a patient with vCJD whose illness onset was within the U.S.A., but was likely acquired in the U.K. The autopsy examination used sodium phosphotungstate precipitation to detect the presence of PrPres. Immunohistochemistry was conducted with the monoclonal antibody 3F4 to the PrP residues 109-112. The presence and absence of PrPres in various tissues are summarized below. Several interesting findings include the presence of PrPres in the kidneys but not the bladder. This is pertinent because small amounts of PrPres have been detected in the urine of animals with prion disease. Also, the two organs are made of different cell types. The urinary bladder is composed of transitional cells, while the kidneys have a small amount of this type of cell. PrPres was also detected in the uterus and ovary, which poses the potential of vertical transmission. Although vertical transmission of BSE has been demonstrated in animals, there has been no evidence of this occurring in humans. These are important findings and they underscore the potential for transmission of vCJD, which we already know can occur in some blood products. Unfortunately, these findings do not tell us anything about the likelihood of transmission as the presence of PrPres has not always equated infectivity. This patient also had a prolonged survival time (32 months), which may have affected the extent of non-neuronal tissue propagation of PrPres. Technorati Tags: prion,variant CJD,vCJD,neuropathology,public health,biology,medicine Notari, S., Moleres, F., Hunter, S., Belay, E., Schonberger, L., Cali, I., Parchi, P., Shieh, W., Brown, P., Zaki, S., Zou, W., & Gambetti, P. (2010). Multiorgan Detection and Characterization of Protease-Resistant Prion Protein in a Case of Variant CJD Examined in the United States PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008765 ... Read more »
Notari, S., Moleres, F., Hunter, S., Belay, E., Schonberger, L., Cali, I., Parchi, P., Shieh, W., Brown, P., Zaki, S.... (2010) Multiorgan Detection and Characterization of Protease-Resistant Prion Protein in a Case of Variant CJD Examined in the United States. PLoS ONE, 5(1). DOI: 10.1371/journal.pone.0008765
- January 2, 2010
- 03:30 PM
- 470 views
Prion Propagation: Survival of the Fittest
by Brian Appleby in CJD Blogger
Once again, a post on the evolutionary relevance of prions… As many of you have likely heard, a recent paper in Science describing the evolutionary properties of prions has been published. It’s importance is twofold: 1) the basic understanding that natural selection may extend beyond the genetic code, and 2) important considerations in the development of treatments for prion diseases. The manuscript describes several experiments in which cloned prion strains developed heterogeneity through the development of mutant strains in the setting of selective pressures. The mutant strains were more “fit” to survive in environments in which selective pressures were applied. This observation was performed in two different contexts. The first experiment involved changing the native environments of prion populations. Prions from brain were transferred to cultured cells and vice versa. In both scenarios, the prion population in its native environment “outcompeted” the rival population (e.g., in cell cultures, cell-derived prions were selected over brain-derived prions). In the second scenario, prions were subjected to swaisonine-free and swaisonine-present environments. Swaisonine is an inhibitor of prion protein conversion. In swaisonine-free environments, swaisonine-sensitive prions predominated whereas swaisonine-resistant prions predominated in the swaisonine-present environment. This was also observed when prion populations were transferred between environments. A rough calculation by the authors estimate a approximate “mutation rate” of 10^-6/doubling. Because prion strains sometimes differ in the sensitivity and site of protease cleavage, these populations were subjected to thermolysin and protease K treatment. However, no differences in structural stabilities were noted, suggesting that these findings are not due to these structural difference seen in between strains but that there is some other property that differentiates these “sub-strains.” These studies show that Darwinian evolution can occur in the absence of what we currently consider genetic information (e.g., nucleic acids). Prions (and perhaps proteins in general) are also subject to selective pressures, mutation, and natural selection based on a “survival of the fittest.” The authors also point out that these findings are important in the development of prion therapeutics as the natural selection observed in these experiments may likely also occur in treatments solely targeting pathological prions. Contrarily, treatments targeting the expression and/or stabilization the native prion protein may be more effective. Li, J., Browning, S., Mahal, S., Oelschlegel, A., & Weissmann, C. (2009). Darwinian Evolution of Prions in Cell Culture Science DOI: 10.1126/science.1183218 Technorati Tags: prion,evolution,natural selection,biology,genetics ... Read more »
Li, J., Browning, S., Mahal, S., Oelschlegel, A., & Weissmann, C. (2009) Darwinian Evolution of Prions in Cell Culture. Science. DOI: 10.1126/science.1183218
- December 19, 2009
- 01:55 PM
- 532 views
Probable vCJD in an individual who was heterozygous at codon 129 of PRNP
by Brian Appleby in CJD Blogger
This week’s Lancet features an article entitled, “Variant CJD in an individual heterozygous for PRNP codon 129” by Kaski and colleagues. The authors report the first case of probable variant Creutzfeldt-Jakob disease (vCJD) in an individual who is heterozygous at codon 129 of the prion protein gene (PRNP). To date, all symptomatic cases have occurred in individuals who are homozygous for methionine at codon 129. As we know from other studies (Brown P, 1994), the incubation period of acquired prion disease varies by the polymorphism at codon 129. Typically, methionine homozygotes have the shortest incubation period and heterozygotes have the longest. Thus one concern that prion researchers have had is whether we would see other incidence peaks of vCJD for other genotypes (Val-Val and Met-Val). Hence, this report is concerning from a public health standpoint in that it occurred in a novel genotype. The case was diagnosed as vCJD due to the young age at onset (30-years-old), clinical presentation (pain sensations and psychiatric symptoms), the presence of the pulvinar sign on brain MRI (Zeidler M, 2000), lack of periodic sharp wave complexes on electroencephalogram, and prolonged survival time (approximately 19 months). An autopsy was not performed, so this is not a definite case of vCJD. Technorati Tags: CJD,Creutzfeldt-Jakob disease,variant CJD,vCJD,prion Kaski, D., Mead, S., Hyare, H., Cooper, S., Jampana, R., Overell, J., Knight, R., Collinge, J., & Rudge, P. (2010). Variant CJD in an individual heterozygous for PRNP codon 129 The Lancet, 374 (9707), 2128-2128 DOI: 10.1016/S0140-6736(09)61568-3 ... Read more »
Kaski, D., Mead, S., Hyare, H., Cooper, S., Jampana, R., Overell, J., Knight, R., Collinge, J., & Rudge, P. (2010) Variant CJD in an individual heterozygous for PRNP codon 129. The Lancet, 374(9707), 2128-2128. DOI: 10.1016/S0140-6736(09)61568-3
- November 24, 2009
- 09:51 AM
- 538 views
The prion protein’s role in neurotransmission
by Brian Appleby in CJD Blogger
As mentioned in a prior post, the exact mechanism of neurotoxicity in prion diseases in unknown. Two possibilities, which are not mutually exclusive, include a loss-of-function of the native prion protein and an acquired neurotoxic effect of the pathologic prion protein. PRNP knockout mice have previously exhibited memory impairment, disruption in circadian rhythms and sleep, behavioral, and neurotransmission changes. Also, excitatory glutamatergic, GABAa receptor-mediated fast inhibition and late afterhyperpolarization have been shown to be reduced or absent in PRNP knockout mice. Rangel and colleagues released a recent study looking at role of the native prion protein specifically in the context of neurotransmission and neuroexcitability. This is the second such in vivo study and the researchers used three populations of mice: 1) wild-type, 2) prion protein gene (PRNP) knock-outs, and PrPc-overexpressing Tg20 mice. In their study, they examined several responses to kainate (KA): seizure activity, electrophysiology, cell death, and gene expression. Both PRNP knockout and Tg20 mice showed susceptibility to KA in the form of onset, frequency, severity, and length of seizures. None of the wildtype mice died whereas one PRNP knockout and two Tg20 mice had severe seizures and expired. Hippocampal cell death was also noted in these two samples. Cell death was restricted to the CA1 and CA3 regions of the hippocampus in PRNP knockout mice and was more global in Tg20 mice. Reactive astrogliosis accompanied neurodegeneration in both samples. No cell death was observed in wild-type mice. Electrophysiological profiles also differed between the groups. There was a strong increase in paired-pulse facilitation and a disappearance of homeostasis in the PRNP knockout and Tg20 mice compared to wild-type mice. detected differences in gene expression profiles between groups. 336 genes were deregulated in the Tg20 mice compared to wild-type mice and PRNP knockouts demonstrated 404 de-regulated genes compared to wild-type mice. 129 genes in the following pathways were co-regulated in PRNP knockout and Tg20 mice: protein ubiquitination, glycerolphospholipid metabolism, nitrogen metabolism, GABA receptor signaling, D-glutamine and D-glutamate metabolism, glutamate receptor signaling, B-cell receptor signaling, hypoxia signaling in the cardiovascular system, and calcium signaling. RT-qPCR studies showed that GABAa and AMPA-kainate receptors were also co-regulated in PRNP knockout and Tg20 mice. In summary, this study shows the importance of the native prion protein in the homeostasis of hippocampal circuits and neuronal transmission, particularly in regards to neuronal excitability. However, too much and too little native prion protein were found to have negative effects in this study. Of note, overexpression of PrPc was performed in PrPres infected mice, which would have altered PrPc amounts. Unfortunately, PrPc levels was not measured in this study. Rangel, A., Madroñal, N., Massó, A., Gavín, R., Llorens, F., Sumoy, L., Torres, J., Delgado-García, J., & Río, J. (2009). Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007592 del.icio.us Tags: neuroscience,prion,genetics,molecular biology,biochemistry,research,biology ... Read more »
Rangel, A., Madroñal, N., Massó, A., Gavín, R., Llorens, F., Sumoy, L., Torres, J., Delgado-García, J., & Río, J. (2009) Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice. PLoS ONE, 4(10). DOI: 10.1371/journal.pone.0007592
- November 23, 2009
- 11:01 AM
- 588 views
Natural selection among us: The Kuru epidemic
by Brian Appleby in CJD Blogger
Kuru is an acquired prion disease, transmitted through ritualistic cannibalism, that reached epidemic proportions in the Fore tribe of Papua New Guinea. In a previous post, I presented an article by John Collinge’s group on the selection process of heterozygosity at codon 129 of the prion protein gene (PRNP). The research group has gone a step further by recently describing a new polymorphism of the PRNP gene, G129V. The authors performed PRNP genotyping of 3,000 individuals from the Eastern Highland population, which included 709 individuals who had participated in cannabalistic rituals. They looked specifically at the codons 127 and 129 among geographic regions and among individuals that were stratified by risk exposure (i.e., high, medium, and low risk). The G127V variant was only found in those regions where kuru was prevalent. 127V was present in half of the women who had the highest exposure to kuru and who were homozygous for methionine at codon 129 (MM). Interesting, although 129V was present in kuru exposed populations, it was not found in those who succumbed to kuru or in unexposed population groups around the world. 127V was also invariably linked to a 129M allele and predominately found in 129MM homozygotes in contrast to 129MV heterozygotes. Heterozygosity at codon 127 thus conveyed resistance to kuru in others susceptible 129MM homozygotes. Thus the newly described G127V polymorphism was naturally selected among populations exposed to kuru as a resistance factor. Both codon 129V and codon 127V are examples of natural selection that have occurred recently. Once again, prion diseases teach us a lot about biology in general…hence another important factor for studying them. Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T, Al-Dujaily H, Hummerich H, Beck J, Mein CA, Verzilli C, Whittaker J, Alpers MP, & Collinge J (2009). A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure. The New England journal of medicine, 361 (21), 2056-2065 PMID: 19923577 del.icio.us Tags: kuru,evolution,epidemiology,prion diseases,research,biology,genetics,risk ... Read more »
Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T, Al-Dujaily H, Hummerich H, Beck J, Mein CA.... (2009) A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure. The New England journal of medicine, 361(21), 2056-2065. PMID: 19923577
- November 14, 2009
- 12:25 PM
- 493 views
Prions activate neuronal cholesterogenic gene expression
by Brian Appleby in CJD Blogger
Herman Schatzl, who recently received an endowed chair at the University of Wyoming, and colleagues published an article in The Journal of Biological Chemistry early this year on the effects of prion proteins on the expression of cholesterol-associated genes. The experiment was an in vitro study using cultured neurons that were infected with the 22L prion strain. They examined gene expression of genes involved in the cholesterol pathway in neurons and supportive cells. The authors found increased transcript levels of at least 9 enzymes within the cholesterol synthesis pathway that was confirmed with real time PCR. Upregulation of theses genes was caused by a prion-dependent increase in the activity and amount of the sterol regulatory element-binding protein (Srebp2), which caused elevated levels of free and total cholesterol. Srebp2 also regulates the expression of low density lipoprotein receptors, which is the main receptor for acquiring extracellular cholesterol. Moreover, downregulation of Srebp2 using siRNA in the absence of exogenous cholesterol decreased prion protein formation compared to cells without siRNA. When external cholesterol was addeded, prion protein levels remained unchanged between cells with and without siRNA. The activation of these genes was specific to neurons, as it was not observed in supportive cells including microglia and astrocytes. These results suggest that prion propagation is associated with cholesterol and that neuronal cells respond to prion infection by upregulating genes involved in cholesterol synthesis. This raises the possibility of using cholesterol modification for treatment purposes, however, this is complicated by the fact that most brain cholesterol is synthesized locally as plasma lipoproteins are restricted from crossing the blood/brain barrier. Bach C, Gilch S, Rost R, Greenwood AD, Horsch M, Hajj GN, Brodesser S, Facius A, Schädler S, Sandhoff K, Beckers J, Leib-Mösch C, Schätzl HM, & Vorberg I (2009). Prion-induced activation of cholesterogenic gene expression by Srebp2 in neuronal cells. The Journal of biological chemistry, 284 (45), 31260-9 PMID: 19748890 del.icio.us Tags: cholesterol,prion,biology,biochemistry,genetics ... Read more »
Bach C, Gilch S, Rost R, Greenwood AD, Horsch M, Hajj GN, Brodesser S, Facius A, Schädler S, Sandhoff K.... (2009) Prion-induced activation of cholesterogenic gene expression by Srebp2 in neuronal cells. The Journal of biological chemistry, 284(45), 31260-9. PMID: 19748890
- November 3, 2009
- 09:54 AM
- 584 views
Components of green tea interfere with the physiologic role of the native prion protein and its conversion into the pathologic prion protein
by Brian Appleby in CJD Blogger
As I continue to catch up on my articles, this post is about an article by Rambold and colleagues that was published in the Journal of Neurochemistry. The researchers’ study was designed to identify compounds that would interfere with the propagation of the pathologic prion protein. The two compounds investigated in the present article were the main components of green tea, epigallocatechin gallate (EGCG) and gallocatechin gallate (GCG). This was an in vitro study that used scrapie-infected N2a (ScN2a) cells. Both EGCG and GCG reduced pathological prion protein in addition to decreasing native prion proteins. In comparison to similar compounds, the authors found that the gallate side chain was necessary for antiprion activity and that an additional hydroxyl group of the trihydroxyphenyl side chain increased depletion of native prion proteins. Their data also indicated that EGCG induced a conformational change in the native prion protein at the plasma membrane that resulted in a transitional conformation that led to internalization and lysosomal degradation. Thus native prion proteins were depleted which also resulted in a reduction of the pathologic prion proteins. An interesting side point was that EGCG decreased the stress-protective function of the native prion protein in uninfected cells. EGCG-treated cells showed an increased vulnerability to stressful conditions (i.e., subjected to excitotoxin kainate, an apoptotic agent) In summary, EGCG and GCG induces a conformation change of the native prion protein that causes it to be internalized and degraded, thereby decreasing its conversion to pathologic prion protein. In this process, the stress-protective activities of the native prion protein are diminished. Once again, the conundrum of pathologic function +/- loss of function questions emerge as the etiologic cause of the neuropathologic process in prion diseases. Rambold, A., Miesbauer, M., Olschewski, D., Seidel, R., Riemer, C., Smale, L., Brumm, L., Levy, M., Gazit, E., Oesterhelt, D., Baier, M., Becker, C., Engelhard, M., Winklhofer, K., & Tatzelt, J. (2008). Green tea extracts interfere with the stress-protective activity of PrP and the formation of PrP Journal of Neurochemistry, 107 (1), 218-229 DOI: 10.1111/j.1471-4159.2008.05611.x del.icio.us Tags: prion,biology,research,biochemistry ... Read more »
Rambold, A., Miesbauer, M., Olschewski, D., Seidel, R., Riemer, C., Smale, L., Brumm, L., Levy, M., Gazit, E., Oesterhelt, D.... (2008) Green tea extracts interfere with the stress-protective activity of PrP and the formation of PrP . Journal of Neurochemistry, 107(1), 218-229. DOI: 10.1111/j.1471-4159.2008.05611.x
- November 2, 2009
- 05:05 PM
- 611 views
A layman’s experience of CJD research
by Brian Appleby in CJD Blogger
I happened across a nice little editorial that was published last year in the British Medical Journal that I am saddened to have not seen sooner. It is a piece written by a father of a 25-year-old who died of variant Creutzfeldt-Jakob disease (vCJD). In this short piece, he describes his experience of being involved in several advisory committees on the treatment of human prion diseases as a layperson. I would like to highlight a few of his comments. First, he was surprised to find out that it was relatively “cutting-edge” to have a layperson involved in the research of clinical trials. And this is in fact true with the exception of some private organizations. He also notes that some researchers were not happy with his appointment, but he took it in stride. After surviving some of the bureaucracy that comes with clinical research, he came to several conclusions: if emerging therapy does not receive institutional support, then it is easy for it to reside outside of the institution's embrace (I would say the same for particularly diseases) National collaboration is essential given the low incidence of CJD cases-he discusses the political nature of having two national organizations work together on a project involvement of laypersons should be welcomed by researchers one must first analyze existing research prior to planning new research “Academic status and fiefdoms must take second place to patients’ interests, particularly when funding for research is coming from the public purse, and there must be a totally open culture of sharing and publication” (my personal favorite) citizens should be encouraged to learn more about clinical trials and to participate in them as a public service Although my research often overlaps with caregivers, I find discussing my research with laypersons one of the most gratifying pieces to doing clinical research. I also tend to agree with having some layperson involvement on clinical research committees, much like how members of the general public are often included on institutional review boards. I’m hoping to get a lot of feedback from this post, so please share your comments below. del.icio.us Tags: prion,CJD,research,advocacy Firkins, L. (2008). The problem in setting research priorities: a layman's experience BMJ, 337 (jul04 1) DOI: 10.1136/bmj.a212 ... Read more »
Firkins, L. (2008) The problem in setting research priorities: a layman's experience. BMJ, 337(jul04 1). DOI: 10.1136/bmj.a212
- October 30, 2009
- 12:08 PM
- 437 views
Anti-prion activity of amphotericin analogues
by Brian Appleby in CJD Blogger
One of several compounds known to inhibit and/or clear pathological prion proteins is amphotericin B. Often called “ampho-terrible” by clinicians because of its toxic side effects, its toxicity has inhibited it from being extensively studied as an anti-prion disease treatment. Its conventional use is as an anti-fungal agent. Soler and colleagues have hence sought to study amphotericin analogues to investigate anti-prion activity in the setting of less toxicity. Analogues were used that had the exocyclic carboxyl groups replaced with methyl groups. The following drugs were studied for their anti-prion effects and toxicity amphotericin B and its analogues 16B and 16-19B as well as amphotericin A and its analogues 8-16A and Tet-aglycone. This was an in vitro study using N2a22L20 cells. Toxicity tests were done by examining cell viability via dye exclusion assays. Both amphotericin B analogues demonstrated less toxicity compared to amphotericin B. Amphotericin A had limited toxicity, but its analogues significantly reduced cell viability. Amphotericin B and both of its analogues demonstrated anti-prion activity with 16-19B having the greatest anti-prion activity. Amphotericin A did not demonstrate anti-prion activity, but both of its analogues did. This study is significant in that it demonstrates anti-prion activity of less toxic amphotericin analogues that may be further studied in regards to possible anti-prion disease treatments. SOLER, L. (2008). Effects of new amphotericin analogues on the scrapie isoform of the prion protein Biochimica et Biophysica Acta (BBA) - General Subjects, 1780 (10), 1162-1167 DOI: 10.1016/j.bbagen.2008.07.005 del.icio.us Tags: prion,amphotericin,treatment,biology ... Read more »
SOLER, L. (2008) Effects of new amphotericin analogues on the scrapie isoform of the prion protein. Biochimica et Biophysica Acta (BBA) - General Subjects, 1780(10), 1162-1167. DOI: 10.1016/j.bbagen.2008.07.005
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