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Stanley B Prusiner - One of the best experts on this subject based on the ideXlab platform.
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guinea pig prion protein supports rapid propagation of bovine spongiform encephalopathy and variant creutzfeldt jakob disease Prions
2016Co-Authors: Joel C Watts, Kurt Giles, Daniel J Saltzberg, Brittany N Dugger, Smita S Patel, Abby Oehler, Sumita Bhardwaj, Andrej Sali, Stanley B PrusinerAbstract:Author(s): Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J; Dugger, Brittany N; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Sali, Andrej; Prusiner, Stanley B | Abstract: The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) Prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD Prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD Prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD Prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD Prions, including the presence of type 2 protease-resistant PrPSc, were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD Prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD Prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates. IMPORTANCE:Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) Prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE Prions but not to sporadic CJD Prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD Prions.
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use of a 2 aminothiazole to treat chronic wasting disease in transgenic mice
2015Co-Authors: David B Berry, Kurt Giles, Sumita Bhardwaj, Abby Oehler, Stephen J Dearmond, Stanley B PrusinerAbstract:Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice infected with Prions that caused scrapie in sheep or Prions that caused chronic wasting disease (CWD; hereafter "CWD Prions") in deer, using 2 isolates for each disease. IND24 doubled the incubation times for mice infected with CWD Prions but had no effect on the survival of those infected with scrapie Prions. Biochemical, neuropathologic, and cell culture analyses were used to characterize prion strain properties following treatment, and results indicated that the CWD Prions were not altered by IND24, regardless of survival extension. These results suggest that IND24 may be a viable candidate for treating CWD in infected captive cervid populations and raise questions about why some prion strains develop drug resistance whereas others do not.
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Mouse Models for Studying the Formation and Propagation of Prions
2014Co-Authors: Joel C Watts, Stanley B PrusinerAbstract:Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of Prions and in assessing candidate therapeutics. The development of transgenic mice that form Prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become Prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses.
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biology and genetics of Prions causing neurodegeneration
2013Co-Authors: Stanley B PrusinerAbstract:Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into Prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some Prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become Prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that Prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.
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protease sensitive synthetic Prions
2010Co-Authors: David W Colby, Giuseppe Legname, Azucena Lemus, Stephen J Dearmond, Rachel Wain, Ilia V Baskakov, Christina G Palmer, Hoangoanh B Nguyen, Fred E Cohen, Stanley B PrusinerAbstract:Prions arise when the cellular prion protein (PrP(C)) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc). Frequently, PrP(Sc) is protease-resistant but protease-sensitive (s) Prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic Prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164), denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174) did not spontaneously generate Prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP(Sc) and caused neurodegeneration. Interestingly, these protease-sensitive Prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600-750 days in Tg4053 mice, which exhibited sPrP(Sc). These novel synthetic Prions demonstrate that conformational changes in wild-type PrP can produce mouse Prions composed exclusively of sPrP(Sc).
John Collinge - One of the best experts on this subject based on the ideXlab platform.
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prion propagation and toxicity in vivo occur in two distinct mechanistic phases
2011Co-Authors: Malin K Sandberg, Huda Aldoujaily, Bernadette Sharps, Anthony R. Clarke, John CollingeAbstract:Here it is shown that during the silent phase of prion infection, Prions first exponentially propagate until a defined limit is reached. Then a plateau phase follows. Prion propagation is independent of prion concentration, whereas in the plateau phase the time to clinical onset is inversely correlated to prion concentration. The similar levels of infectivity at the end of the first and second phase suggests that there is a separation between prion infectivity and toxicity. Moreover, something seems to limit prion production. It is suggested that the Prions are not neurotoxic themselves but catalyse the formation of such species from PrPC. Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity to a toxic pathway.
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highly sensitive quantitative cell based assay for Prions adsorbed to solid surfaces
2009Co-Authors: Julie Ann Edgeworth, Anthony R. Clarke, Charles Weissmann, Graham S Jackson, John CollingeAbstract:Prions are comprised principally of aggregates of a misfolded host protein and cause fatal transmissible neurodegenerative disorders of humans and animals, such as variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Prions pose significant public health concerns, including contamination of blood products and surgical instruments; require laborious and often insensitive animal bioassay to detect; and resist conventional hospital sterilization methods. A major experimental advance was the cell culture-based scrapie cell assay, allowing prion titres to be estimated more precisely and an order of magnitude faster than by animal bioassays. Here we describe a bioassay method that exploits the marked binding affinity of Prions to steel surfaces. Using steel wires as a concentrating and sensitization tool and combining with an adapted scrapie cell endpoint assay we can achieve, for mouse Prions, a sensitivity 100× higher than that achieved in standard mouse bioassays. The rapidity and sensitivity of this assay offers a major advance over small animal bioassay in many aspects of prion research. In addition, its specific application in assay of metal-bound Prions allows evaluation of novel prion decontamination methods.
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Prion infectivity in variant Creutzfeldt-Jakob disease rectum
2007Co-Authors: John CollingeAbstract:Background: Disease-related prion protein (PrPSc) is readily detectable in lymphoreticular tissues in variant Creutzfeldt-Jakob disease (vCJD), but not in other forms of human prion disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic vCJD infection, has led to significant concerns that secondary transmission of vCJD Prions will occur through a wide range of surgical procedures. To date PrPSc: prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD Prions are similar to experimental rodent Prions, where PrPSc concentration typically reflects infectious prion titre.Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrPSc.Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M(+/+) Prnp(o/o))-35 and Tg(HuPrP129M(+/+) Prnp(o/o))-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrPSc that have been observed in vCJD.Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrPSc at a concentration of 10(4.7)-fold lower than that in vCJD brain.Conclusions: These data confirm the potential risks for secondary transmission of vCJD Prions via gastrointestinal procedures and support the use of PrPSc as a quantitative marker of prion infectivity in vCJD tissues.
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prion infectivity in variant creutzfeldt jakob disease rectum commentary
2007Co-Authors: M W Head, Emmanuel A Asante, Melanie Desbruslais, Jacqueline M Linehan, Jonathan D F Wadsworth, Susan Joiner, James W Ironside, Katie Fox, S Brandner, John CollingeAbstract:Background: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues in variant Creutzfeldt-Jakob disease (vCJD), but not in other forms of human prion disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic VCJD infection, has led to significant concerns that secondary transmission of vCJD Prions will occur through a wide range of surgical procedures. To date PrP Sc :prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD Prions are similar to experimental rodent Prions, where PrP Sc concentration typically reflects infectious prion titre. Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrP Sc . Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M +/+ Prnp°/°)-35 and Tg(HuPrP129M +/ + Prnp °/° )-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrP Sc that have been observed in vCJD. Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrP Sc at a concentration of 10 4.7 -fold lower than that in vCJD brain. Conclusions: These data confirm the potential risks for secondary transmission of vCJD Prions via gastrointestinal procedures and support the use of PrP Sc as a quantitative marker of prion infectivity in vCJD tissues.
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Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice
2006Co-Authors: John CollingeAbstract:All neuropathologically confirmed cases of variant Creutzfeldt-Jakob disease (vCJD), characterized by abundant florid plaques and type 4 disease-related prion protein (PrPSc) in the brain, have been homozygous for methionine at polymorphic residue 129 of PRNP. The distinctive neuropathological and molecular phenotype of vCJD can be faithfully recapitulated in Prnp-null transgenic mice homozygous for human PrP M129 but not V129, where a distinct prion strain is propagated. Here we model susceptibility of 129MV heterozygotes, the most common PRNP genotype, in transgenic mice and show that, remarkably, propagation of type 4 PrPSc was not associated with characteristic vCJD neuropathology. Depending on the source of the inoculum these mice can develop four distinct disease phenotypes after challenge with bovine spongiform encephalopathy (BSE) Prions or vCJD (human-passaged BSE) Prions. vCJD-challenged mice had higher attack rates of prion infection than BSE-challenged recipients. These data argue that human PRNP 129 heterozygotes will be more susceptible to infection with vCJD Prions than to cattle BSE Prions and may present with a neuropathological phenotype distinct from vCJD.
Jacqueline M Linehan - One of the best experts on this subject based on the ideXlab platform.
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a naturally occurring variant of the human prion protein completely prevents prion disease
2015Co-Authors: Emmanuel A Asante, Michelle Smidak, Andrew Grimshaw, Richard Houghton, Asif Jeelani, Tatiana Jakubcova, Shyma Hamdan, Angela Richardlondt, Andrew Tomlinson, Jacqueline M LinehanAbstract:This study looks at a polymorphism of the human prion protein gene, which results in a G-to-V substitution at residue 127, in transgenic mice expressing different human prion proteins, finding that mice heterozygous for the G127V polymorphism are resistant to both kuru and classical CJD Prions, but there is some transmission of variant CJD Prions; most remarkable, however, is that mice homozygous for V127 are completely resistant to all prion strains.
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a naturally occurring variant of the human prion protein completely prevents prion disease
2015Co-Authors: Emmanuel A Asante, Michelle Smidak, Andrew Grimshaw, Richard Houghton, Asif Jeelani, Tatiana Jakubcova, Shyma Hamdan, Angela Richardlondt, Andrew Tomlinson, Jacqueline M LinehanAbstract:Mammalian Prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) Prions (which are closely similar) but can be infected with variant CJD Prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy Prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.
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atypical scrapie Prions from sheep and lack of disease in transgenic mice overexpressing human prion protein
2013Co-Authors: Jonathan D F Wadsworth, Jacqueline M Linehan, Susan Joiner, Anne Balkemabuschmann, John Spiropoulos, Marion Simmons, Peter C Griffiths, Martin H Groschup, James Hope, Sebastian BrandnerAbstract:Public and animal health controls to limit human exposure to animal Prions are focused on bovine spongiform encephalopathy (BSE), but other prion strains in ruminants may also have zoonotic potential. One example is atypical/Nor98 scrapie, which evaded statutory diagnostic methods worldwide until the early 2000s. To investigate whether sheep infected with scrapie Prions could be another source of infection, we inoculated transgenic mice that overexpressed human prion protein with brain tissue from sheep with natural field cases of classical and atypical scrapie, sheep with experimental BSE, and cattle with BSE. We found that these mice were susceptible to BSE Prions, but disease did not develop after prolonged postinoculation periods when mice were inoculated with classical or atypical scrapie Prions. These data are consistent with the conclusion that prion disease is less likely to develop in humans after exposure to naturally occurring Prions of sheep than after exposure to epizootic BSE Prions of ruminants.
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chronic wasting disease Prions are not transmissible to transgenic mice overexpressing human prion protein
2010Co-Authors: Malin K Sandberg, Emmanuel A Asante, Huda Aldoujaily, Christina J Sigurdson, Jacqueline M Linehan, Markus Glatzel, Catherine Omalley, Caroline Powell, Sebastian Brandner, Jonathan D F WadsworthAbstract:Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD-infected cervids have been reported in 14 USA states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD Prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD Prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice overexpressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilized in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD Prions, allowing comparison with CWD. Here, we show that these mice proved entirely resistant to infection with mule deer CWD Prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE Prions. However, it is possible that CWD may be caused by multiple prion strains. Further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterized.
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prion infectivity in variant creutzfeldt jakob disease rectum commentary
2007Co-Authors: M W Head, Emmanuel A Asante, Melanie Desbruslais, Jacqueline M Linehan, Jonathan D F Wadsworth, Susan Joiner, James W Ironside, Katie Fox, S Brandner, John CollingeAbstract:Background: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular tissues in variant Creutzfeldt-Jakob disease (vCJD), but not in other forms of human prion disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic VCJD infection, has led to significant concerns that secondary transmission of vCJD Prions will occur through a wide range of surgical procedures. To date PrP Sc :prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD Prions are similar to experimental rodent Prions, where PrP Sc concentration typically reflects infectious prion titre. Aim: To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrP Sc . Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M +/+ Prnp°/°)-35 and Tg(HuPrP129M +/ + Prnp °/° )-45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrP Sc that have been observed in vCJD. Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrP Sc at a concentration of 10 4.7 -fold lower than that in vCJD brain. Conclusions: These data confirm the potential risks for secondary transmission of vCJD Prions via gastrointestinal procedures and support the use of PrP Sc as a quantitative marker of prion infectivity in vCJD tissues.
Glenn C Telling - One of the best experts on this subject based on the ideXlab platform.
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prion disease is accelerated in mice lacking stress induced heat shock protein 70 hsp70
2019Co-Authors: Charles E Mays, Enrique Armijo, Rodrigo Morales, Carlos Kramm, Andrea Flores, Anjana Tiwari, Jifeng Bian, Glenn C TellingAbstract:Prion diseases are a group of incurable neurodegenerative disorders that affect humans and animals via infection with proteinaceous particles called Prions. Prions are composed of PrPSc, a misfolded version of the cellular prion protein (PrPC). During disease progression, PrPSc replicates by interacting with PrPC and inducing its conversion to PrPSc. As PrPSc accumulates, cellular stress mechanisms are activated to maintain cellular proteostasis, including increased protein chaperone levels. However, the exact roles of several of these chaperones remain unclear. Here, using various methodologies to monitor prion replication (i.e. protein misfolding cyclic amplification and cellular and animal infectivity bioassays), we studied the potential role of the molecular chaperone heat shock protein 70 (HSP70) in prion replication in vitro and in vivo. Our results indicated that pharmacological induction of the heat shock response in cells chronically infected with Prions significantly decreased PrPSc accumulation. We also found that HSP70 alters prion replication in vitro. More importantly, prion infection of mice lacking the genes encoding stress-induced HSP70 exhibited accelerated prion disease progression compared with WT mice. In parallel with HSP70 being known to respond to endogenous and exogenous stressors such as heat, infection, toxicants, and ischemia, our results indicate that HSP70 may also play an important role in suppressing or delaying prion disease progression, opening opportunities for therapeutic intervention.
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quinacrine promotes replication and conformational mutation of chronic wasting disease Prions
2014Co-Authors: Jifeng Bian, Haeeun Kang, Glenn C TellingAbstract:Quinacrine’s ability to reduce levels of pathogenic prion protein (PrPSc) in mouse cells infected with experimentally adapted Prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrPSc accumulation and promotes propagation of Prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting Prions produced prolonged incubation times and altered PrPSc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD Prions were comprised of an altered PrPSc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of Prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining Prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.
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chronic wasting disease Prions in elk antler velvet
2009Co-Authors: Rachel Angers, Katherine I Orourke, Tanya Seward, Dana Napie, Michael Gree, Edward A Hoove, Terry R Sprake, Aru Alachandra, Glenn C TellingAbstract:Chronic wasting disease (CWD) is a contagious, fatal prion disease of deer and elk that continues to emerge in new locations. To explore the means by which Prions are transmitted with high efficiency among cervids, we examined prion infectivity in the apical skin layer covering the growing antler (antler velvet) by using CWD-susceptible transgenic mice and protein misfolding cyclic amplification. Our finding of Prions in antler velvet of CWD-affected elk suggests that this tissue may play a role in disease transmission among cervids. Humans who consume antler velvet as a nutritional supplement are at risk for exposure to Prions. The fact that CWD prion incubation times in transgenic mice expressing elk prion protein are consistently more rapid raises the possibility that residue 226, the sole primary structural difference between deer and elk prion protein, may be a major determinant of CWD pathogenesis.
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the elk prnp codon 132 polymorphism controls cervid and scrapie prion propagation
2008Co-Authors: Kristi M Green, Shawn Browning, Tanya Seward, Edward A Hoover, Jean E Jewell, Dana L Ross, Michael A Green, Elizabeth S Williams, Glenn C TellingAbstract:The elk prion protein gene (PRNP) encodes either methionine (M) or leucine (L) at codon 132, the L132 allele apparently affording protection against chronic wasting disease (CWD). The corresponding human codon 129 polymorphism influences the host range of bovine spongiform encephalopathy (BSE) Prions. To fully address the influence of this cervid polymorphism on CWD pathogenesis, we created transgenic (Tg) mice expressing cervid PrPC with L at residue 132, referred to as CerPrPC-L132, and compared the transmissibility of CWD Prions from elk of defined PRNP genotypes, namely homozygous M/M or L/L or heterozygous M/L, in these Tg mice with previously described Tg mice expressing CerPrPC-M132, referred to as Tg(CerPrP) mice. While Tg(CerPrP) mice were consistently susceptible to CWD Prions from elk of all three genotypes, Tg(CerPrP-L132) mice uniformly failed to develop disease following challenge with CWD Prions. In contrast, SSBP/1 sheep scrapie Prions transmitted efficiently to both Tg(CerPrP) and Tg(CerPrP-L132) mice. Our findings suggest that the elk 132 polymorphism controls prion susceptibility at the level of prion strain selection and that cervid PrP L132 severely restricts propagation of CWD Prions. We speculate that the L132 polymorphism results in less efficient conversion of CerPrPC-L132 by CWD Prions, an effect that is overcome by the SSBP/1 strain. Our studies show the accumulation of subclinical levels of CerPrPSc in aged asymptomatic CWD-inoculated Tg(CerPrP-L132) mice and also suggests the establishment of a latent infection state in apparently healthy elk expressing this seemingly protective allele.
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abbreviated incubation times for human Prions in mice expressing a chimeric mouse human prion protein transgene
2003Co-Authors: Carsten Korth, Darlene Groth, Glenn C Telling, Kiyotoshi Kaneko, Norbert Heye, James A Mastrianni, Piero ParchiAbstract:Transgenic (Tg) mouse lines that express chimeric mouse–human prion protein (PrP), designated MHu2M, are susceptible to Prions from patients with sporadic Creutzfeldt–Jakob disease (sCJD). With the aim of decreasing the incubation time to fewer than 200 days, we constructed transgenes in which one or more of the nine human residues in MHu2M were changed to mouse. The construct with murine residues at positions 165 and 167 was expressed in Tg(MHu2M,M165V,E167Q) mice and resulted in shortening the incubation time to ≈110 days for Prions from sCJD patients. The construct with a murine residue at position 96 resulted in lengthening the incubation time to more than 280 days for sCJD Prions. When murine residues 96, 165, and 167 were expressed, the abbreviated incubation times for sCJD Prions were abolished. Variant CJD Prions showed prolonged incubation times between 300 and 700 days in Tg(MHu2M) mice on first passage and incubation times of ≈350 days in Tg(MHu2M,M165V,E167Q) mice. On second and third passages of variant CJD Prions in Tg(MHu2M) mice, multiple strains of Prions were detected based on incubation times and the sizes of the protease-resistant, deglycosylated PrPSc fragments. Our discovery of a previously undescribed chimeric transgene with abbreviated incubation times for sCJD Prions should facilitate studies on the prion species barrier and human prion diversity.
Susan Lindquist - One of the best experts on this subject based on the ideXlab platform.
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luminidependens ld is an arabidopsis protein with prion behavior
2016Co-Authors: Sohini Chakrabortee, Marc L Mendillo, Can Kayatekin, Alex K Lancaster, Gregory A Newby, Susan LindquistAbstract:Prion proteins provide a unique mode of biochemical memory through self-perpetuating changes in protein conformation and function. They have been studied in fungi and mammals, but not yet identified in plants. Using a computational model, we identified candidate prion domains (PrDs) in nearly 500 plant proteins. Plant flowering is of particular interest with respect to biological memory, because its regulation involves remembering and integrating previously experienced environmental conditions. We investigated the prion-forming capacity of three prion candidates involved in flowering using a yeast model, where prion attributes are well defined and readily tested. In yeast, Prions heritably change protein functions by templating monomers into higher-order assemblies. For most yeast Prions, the capacity to convert into a prion resides in a distinct prion domain. Thus, new prion-forming domains can be identified by functional complementation of a known prion domain. The prion-like domains (PrDs) of all three of the tested proteins formed higher-order oligomers. Uniquely, the Luminidependens PrD (LDPrD) fully replaced the prion-domain functions of a well-characterized yeast prion, Sup35. Our results suggest that prion-like conformational switches are evolutionarily conserved and might function in a wide variety of normal biological processes.
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Prions are a common mechanism for phenotypic inheritance in wild yeasts
2012Co-Authors: Randal Halfmann, Alex K Lancaster, Susan Lindquist, Daniel F Jarosz, Sandra K Jones, Amelia N ChangAbstract:The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast Prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare 'diseases' of laboratory cultivation. Here we biochemically test approximately 700 wild strains of Saccharomyces for [PSI(+)] or [MOT3(+)], and find these Prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one-third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, Prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities.
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Prions protein homeostasis and phenotypic diversity
2010Co-Authors: Randal Halfmann, Susan Lindquist, Simon AlbertiAbstract:Prions are fascinating but often misunderstood protein aggregation phenomena. The traditional association of the mammalian prion protein with disease has overshadowed a potentially more interesting attribute of Prions: their ability to create protein-based molecular memories. In fungi, Prions alter the relationship between genotype and phenotype in a heritable way that diversifies clonal populations. Recent findings in yeast indicate that Prions might be much more common than previously realized. Moreover, prion-driven phenotypic diversity increases under stress, and can be amplified by the dynamic maturation of prion-initiating states. In this article, we suggest that these qualities allow Prions to act as ‘bet-hedging' devices that facilitate the adaptation of yeasts to stressful environments, and might speed the evolution of new traits.
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Destruction or Potentiation of Different Prions Catalyzed by Similar Hsp104 Remodeling Activities
2006Co-Authors: James Shorter, Susan LindquistAbstract:Yeast Prions are protein-based genetic elements that self-perpetuate changes in protein conformation and function. A protein-remodeling factor, Hsp104, controls the inheritance of several yeast Prions, including those formed by Sup35 and Ure2. Perplexingly, deletion of Hsp104 eliminates Sup35 and Ure2 Prions, whereas overexpression of Hsp104 purges cells of Sup35 Prions, but not Ure2 Prions. Here, we used pure components to dissect how Hsp104 regulates prion formation, growth, and division. For both Sup35 and Ure2, Hsp104 catalyzes de novo prion nucleation from soluble, native protein. Using a distinct mechanism, Hsp104 fragments both Prions to generate new prion assembly surfaces. For Sup35, the fragmentation endpoint is an ensemble of noninfectious, amyloid-like aggregates and soluble protein that cannot replicate conformation. In vivid distinction, the endpoint of Ure2 fragmentation is short prion fibers with enhanced infectivity and self-replicating ability. These advances explain the distinct effects of Hsp104 on the inheritance of the two Prions.
