The Experts below are selected from a list of 183 Experts worldwide ranked by ideXlab platform
Ilia V Baskakov - One of the best experts on this subject based on the ideXlab platform.
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Prion replication environment defines the fate of prion strain adaptation.
Public Library of Science (PLoS), 2018Co-Authors: Elizaveta Katorcha, Gabor G. Kovacs, Natallia Makarava, Nuria Gonzalez-montalban, Ilia V BaskakovAbstract:The main risk of emergence of prion diseases in humans is associated with a cross-species Transmission of prions of zoonotic origin. Prion Transmission between species is regulated by a species barrier. Successful cross-species Transmission is often accompanied by strain adaptation and result in stable changes of strain-specific disease phenotype. Amino acid sequences of host PrPC and donor PrPSc as well as strain-specific structure of PrPSc are believed to be the main factors that control species barrier and strain adaptation. Yet, despite our knowledge of the primary structures of mammalian prions, predicting the fate of prion strain adaptation is very difficult if possible at all. The current study asked the question whether changes in cofactor environment affect the fate of prions adaptation. To address this question, hamster strain 263K was propagated under normal or RNA-depleted conditions using Serial Protein Misfolding Cyclic Amplification (PMCA) conducted first in mouse and then hamster substrates. We found that 263K propagated under normal conditions in mouse and then hamster substrates induced the disease phenotype similar to the original 263K. Surprisingly, 263K that propagated first in RNA-depleted mouse substrate and then normal hamster substrate produced a new disease phenotype upon Serial Transmission. Moreover, 263K that propagated in RNA-depleted mouse and then RNA-depleted hamster substrates failed to induce clinical diseases for three Serial passages despite a gradual increase of PrPSc in animals. To summarize, depletion of RNA in prion replication reactions changed the rate of strain adaptation and the disease phenotype upon subsequent Serial passaging of PMCA-derived materials in animals. The current studies suggest that replication environment plays an important role in determining the fate of prion strain adaptation
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cross seeding of prions by aggregated α synuclein leads to transmissible spongiform encephalopathy
PLOS Pathogens, 2017Co-Authors: Elizaveta Katorcha, Gabor G. Kovacs, Natallia Makarava, Young Jin Lee, Iris Lindberg, Mervyn J Monteiro, Ilia V BaskakovAbstract:Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, prion and other diseases. Recent years have witnessed a growing number of reports of overlap in neuropathological features that were once thought to be unique to only one neurodegenerative disorder. However, the origin for the overlap remains unclear. One possibility is that diseases with mixed brain pathologies might arise from cross-seeding of one amyloidogenic protein by aggregated states of unrelated proteins. In the current study we examined whether prion replication can be induced by cross-seeding by α-synuclein or Aβ peptide. We found that α-synuclein aggregates formed in cultured cells or in vitro display cross-seeding activity and trigger misfolding of the prion protein (PrPC) in Serial Protein Misfolding Cyclic Amplification reactions, producing self-replicating PrP states characterized by a short C-terminal proteinase K (PK)-resistant region referred to as PrPres. Non-fibrillar α-synuclein or fibrillar Aβ failed to cross-seed misfolding of PrPC. Remarkably, PrPres triggered by aggregated α-synuclein in vitro propagated in animals and, upon Serial Transmission, produced PrPSc and clinical prion disease characterized by spongiosis and astrocytic gliosis. The current study demonstrates that aggregated α-synuclein is potent in cross-seeding of prion protein misfolding and aggregation in vitro, producing self-replicating states that can lead to transmissible prion diseases upon Serial passaging in wild type animals. In summary, the current work documents direct cross-seeding between unrelated amyloidogenic proteins associated with different neurodegenerative diseases. This study suggests that early interaction between unrelated amyloidogenic proteins might underlie the etiology of mixed neurodegenerative proteinopathies.
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selective amplification of classical and atypical prions using modified protein misfolding cyclic amplification
Journal of Biological Chemistry, 2013Co-Authors: Natallia Makarava, Regina Savtchenko, Ilia V BaskakovAbstract:Abstract With the development of Protein Misfolding Cyclic Amplification (PMCA), the topic of faithful propagation of prion strain-specific structures has been constantly debated. Here we show that by subjecting brain material of a synthetic strain consisting of a mixture of self-replicating states to PMCAb, selective amplification of PrPSc could be achieved, and that PMCAb mimicked the evolutionary trend observed during Serial Transmission in animals. On the other hand, using modified PMCAb conditions that employ partially deglycosylagted PrPC (dgPMCAb), an alternative transmissible state referred to as atypical PrPres was selectively amplified from a mixture. Surprisingly, when hamster-adapted strains (263K and Hyper) were subjected to dgPMCAb, their proteinase K (PK) digestion profile underwent a dramatic transformation suggesting that a mixture of atypical PrPres and PrPSc might be present in brain-derived materials. However, detailed analysis revealed that the PK-resistant profile of PrPSc changed in response to dgPMCAb. Despite these changes, the 263K strain-specific disease phenotype was preserved after passage through dgPMCAb. This study revealed that the change in PrPSc biochemical phenotype does not always represent an irreversible transformation of a strain, but rather demonstrated the existence of a wide range of variation for strain-specific physical features in response to a change in prion replication environment. The current work introduced a new PMCA technique for amplification of atypical PrPres, and raised a number of questions about the need for a clever distinction between actual strain mutation and variation of strain-specific features in response to a change in the replication environment.
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Recombinant prion protein induces a new transmissible prion disease in wild-type animals
Acta Neuropathologica, 2010Co-Authors: Natallia Makarava, Gabor G. Kovacs, Olga Bocharova, Regina Savtchenko, Irina Alexeeva, Herbert Budka, Robert G. Rohwer, Ilia V BaskakovAbstract:Prion disease is a neurodegenerative malady, which is believed to be transmitted via a prion protein in its abnormal conformation (PrP^Sc). Previous studies have failed to demonstrate that prion disease could be induced in wild-type animals using recombinant prion protein (rPrP) produced in Escherichia coli . Here, we report that prion infectivity was generated in Syrian hamsters after inoculating full-length rPrP that had been converted into the cross-β-sheet amyloid form and subjected to annealing. Serial Transmission gave rise to a disease phenotype with highly unique clinical and neuropathological features. Among them were the deposition of large PrP^Sc plaques in subpial and subependymal areas in brain and spinal cord, very minor lesioning of the hippocampus and cerebellum, and a very slow progression of disease after onset of clinical signs despite the accumulation of large amounts of PrP^Sc in the brain. The length of the clinical duration is more typical of human and large animal prion diseases, than those of rodents. Our studies establish that transmissible prion disease can be induced in wild-type animals by inoculation of rPrP and introduce a valuable new model of prion diseases.
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
Journal of Virology, 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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Serial Transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Karen K Hsiao, Darlene Groth, Michael R Scott, Shulian Yang, Hana Serban, Dennis Rapp, Dallas Foster, Marilyn Torchia, Stephen J Dearmond, Stanley B PrusinerAbstract:Two lines of transgenic (Tg) mice expressing high (H) levels of the mutant P101L prion protein (PrP) developed a neurologic illness and central nervous system pathology indistinguishable from experimental murine scrapie; these mice were designated Tg(MoPrP-P101L)H. Brain homogenates from Tg(MoPrP-P101L)H mice were inoculated intracerebrally into CD-1 Swiss mice, Syrian hamsters, and Tg196 mice, Tg mice expressing the MoPrP-P101L transgene at low levels. None of the CD-1 mice developed central nervous system dysfunction, whereas approximately 10% of hamsters and approximately 40% of the Tg196 mice manifested neurologic signs between 117 and 639 days after inoculation. Serial Transmission of neurodegeneration in Tg196 mice and Syrian hamsters was initiated with brain extracts, producing incubation times of approximately 400 and approximately 75 days, respectively. Although the Tg(MoPrP-P101L)H mice appear to accumulate only low levels of infections prions in their brains, the Serial Transmission of disease to inoculated recipients argues that prion formation occurs de novo in the brains of these uninoculated animals. These Tg mouse studies, taken together with similar findings in humans dying of inherited prion diseases, provide additional evidence that prions lack a foreign nucleic acid.
Anthony G Phillips - One of the best experts on this subject based on the ideXlab platform.
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thalamic cortical striatal circuitry subserves working memory during delayed responding on a radial arm maze
The Journal of Neuroscience, 1999Co-Authors: Stan B Floresco, Deanna N Braaksma, Anthony G PhillipsAbstract:The medial dorsal nuclei of the thalamus (MDNt), the prefrontal cortex, and the ventral striatum form an interconnected neural circuit that may subserve certain types of working memory. The present series of experiments investigated functional interactions between these brain regions in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. In Experiment 1, transient inactivation of the MDNt by a bilateral injection of lidocaine selectively disrupted performance on a delayed task but not on a nondelayed random foraging version of the radial arm maze task. In Experiment 2, asymmetrical lidocaine injections into the MDNt on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task. Similarly, disconnections between the prefrontal cortex and the nucleus accumbens also disrupted foraging on this task, whereas disconnections between the MDNt and the nucleus accumbens had no effect. These data suggest that Serial Transmission of information among the MDNt, the prefrontal cortex, and the nucleus accumbens is required when trial-unique, short-term spatial memory is used to guide prospective search behavior. The results are discussed with respect to a distributed neural network linking limbic, thalamic, cortical, and striatal regions, which mediates executive functions of working memory.
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selective roles for hippocampal prefrontal cortical and ventral striatal circuits in radial arm maze tasks with or without a delay
The Journal of Neuroscience, 1997Co-Authors: Stan B Floresco, Jeremy K Seamans, Anthony G PhillipsAbstract:The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The two-phase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that Serial Transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on Serial Transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbic–cortical–striatal networks.
Natallia Makarava - One of the best experts on this subject based on the ideXlab platform.
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Prion replication environment defines the fate of prion strain adaptation.
Public Library of Science (PLoS), 2018Co-Authors: Elizaveta Katorcha, Gabor G. Kovacs, Natallia Makarava, Nuria Gonzalez-montalban, Ilia V BaskakovAbstract:The main risk of emergence of prion diseases in humans is associated with a cross-species Transmission of prions of zoonotic origin. Prion Transmission between species is regulated by a species barrier. Successful cross-species Transmission is often accompanied by strain adaptation and result in stable changes of strain-specific disease phenotype. Amino acid sequences of host PrPC and donor PrPSc as well as strain-specific structure of PrPSc are believed to be the main factors that control species barrier and strain adaptation. Yet, despite our knowledge of the primary structures of mammalian prions, predicting the fate of prion strain adaptation is very difficult if possible at all. The current study asked the question whether changes in cofactor environment affect the fate of prions adaptation. To address this question, hamster strain 263K was propagated under normal or RNA-depleted conditions using Serial Protein Misfolding Cyclic Amplification (PMCA) conducted first in mouse and then hamster substrates. We found that 263K propagated under normal conditions in mouse and then hamster substrates induced the disease phenotype similar to the original 263K. Surprisingly, 263K that propagated first in RNA-depleted mouse substrate and then normal hamster substrate produced a new disease phenotype upon Serial Transmission. Moreover, 263K that propagated in RNA-depleted mouse and then RNA-depleted hamster substrates failed to induce clinical diseases for three Serial passages despite a gradual increase of PrPSc in animals. To summarize, depletion of RNA in prion replication reactions changed the rate of strain adaptation and the disease phenotype upon subsequent Serial passaging of PMCA-derived materials in animals. The current studies suggest that replication environment plays an important role in determining the fate of prion strain adaptation
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cross seeding of prions by aggregated α synuclein leads to transmissible spongiform encephalopathy
PLOS Pathogens, 2017Co-Authors: Elizaveta Katorcha, Gabor G. Kovacs, Natallia Makarava, Young Jin Lee, Iris Lindberg, Mervyn J Monteiro, Ilia V BaskakovAbstract:Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, prion and other diseases. Recent years have witnessed a growing number of reports of overlap in neuropathological features that were once thought to be unique to only one neurodegenerative disorder. However, the origin for the overlap remains unclear. One possibility is that diseases with mixed brain pathologies might arise from cross-seeding of one amyloidogenic protein by aggregated states of unrelated proteins. In the current study we examined whether prion replication can be induced by cross-seeding by α-synuclein or Aβ peptide. We found that α-synuclein aggregates formed in cultured cells or in vitro display cross-seeding activity and trigger misfolding of the prion protein (PrPC) in Serial Protein Misfolding Cyclic Amplification reactions, producing self-replicating PrP states characterized by a short C-terminal proteinase K (PK)-resistant region referred to as PrPres. Non-fibrillar α-synuclein or fibrillar Aβ failed to cross-seed misfolding of PrPC. Remarkably, PrPres triggered by aggregated α-synuclein in vitro propagated in animals and, upon Serial Transmission, produced PrPSc and clinical prion disease characterized by spongiosis and astrocytic gliosis. The current study demonstrates that aggregated α-synuclein is potent in cross-seeding of prion protein misfolding and aggregation in vitro, producing self-replicating states that can lead to transmissible prion diseases upon Serial passaging in wild type animals. In summary, the current work documents direct cross-seeding between unrelated amyloidogenic proteins associated with different neurodegenerative diseases. This study suggests that early interaction between unrelated amyloidogenic proteins might underlie the etiology of mixed neurodegenerative proteinopathies.
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selective amplification of classical and atypical prions using modified protein misfolding cyclic amplification
Journal of Biological Chemistry, 2013Co-Authors: Natallia Makarava, Regina Savtchenko, Ilia V BaskakovAbstract:Abstract With the development of Protein Misfolding Cyclic Amplification (PMCA), the topic of faithful propagation of prion strain-specific structures has been constantly debated. Here we show that by subjecting brain material of a synthetic strain consisting of a mixture of self-replicating states to PMCAb, selective amplification of PrPSc could be achieved, and that PMCAb mimicked the evolutionary trend observed during Serial Transmission in animals. On the other hand, using modified PMCAb conditions that employ partially deglycosylagted PrPC (dgPMCAb), an alternative transmissible state referred to as atypical PrPres was selectively amplified from a mixture. Surprisingly, when hamster-adapted strains (263K and Hyper) were subjected to dgPMCAb, their proteinase K (PK) digestion profile underwent a dramatic transformation suggesting that a mixture of atypical PrPres and PrPSc might be present in brain-derived materials. However, detailed analysis revealed that the PK-resistant profile of PrPSc changed in response to dgPMCAb. Despite these changes, the 263K strain-specific disease phenotype was preserved after passage through dgPMCAb. This study revealed that the change in PrPSc biochemical phenotype does not always represent an irreversible transformation of a strain, but rather demonstrated the existence of a wide range of variation for strain-specific physical features in response to a change in prion replication environment. The current work introduced a new PMCA technique for amplification of atypical PrPres, and raised a number of questions about the need for a clever distinction between actual strain mutation and variation of strain-specific features in response to a change in the replication environment.
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Recombinant prion protein induces a new transmissible prion disease in wild-type animals
Acta Neuropathologica, 2010Co-Authors: Natallia Makarava, Gabor G. Kovacs, Olga Bocharova, Regina Savtchenko, Irina Alexeeva, Herbert Budka, Robert G. Rohwer, Ilia V BaskakovAbstract:Prion disease is a neurodegenerative malady, which is believed to be transmitted via a prion protein in its abnormal conformation (PrP^Sc). Previous studies have failed to demonstrate that prion disease could be induced in wild-type animals using recombinant prion protein (rPrP) produced in Escherichia coli . Here, we report that prion infectivity was generated in Syrian hamsters after inoculating full-length rPrP that had been converted into the cross-β-sheet amyloid form and subjected to annealing. Serial Transmission gave rise to a disease phenotype with highly unique clinical and neuropathological features. Among them were the deposition of large PrP^Sc plaques in subpial and subependymal areas in brain and spinal cord, very minor lesioning of the hippocampus and cerebellum, and a very slow progression of disease after onset of clinical signs despite the accumulation of large amounts of PrP^Sc in the brain. The length of the clinical duration is more typical of human and large animal prion diseases, than those of rodents. Our studies establish that transmissible prion disease can be induced in wild-type animals by inoculation of rPrP and introduce a valuable new model of prion diseases.
Stan B Floresco - One of the best experts on this subject based on the ideXlab platform.
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thalamic cortical striatal circuitry subserves working memory during delayed responding on a radial arm maze
The Journal of Neuroscience, 1999Co-Authors: Stan B Floresco, Deanna N Braaksma, Anthony G PhillipsAbstract:The medial dorsal nuclei of the thalamus (MDNt), the prefrontal cortex, and the ventral striatum form an interconnected neural circuit that may subserve certain types of working memory. The present series of experiments investigated functional interactions between these brain regions in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. In Experiment 1, transient inactivation of the MDNt by a bilateral injection of lidocaine selectively disrupted performance on a delayed task but not on a nondelayed random foraging version of the radial arm maze task. In Experiment 2, asymmetrical lidocaine injections into the MDNt on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task. Similarly, disconnections between the prefrontal cortex and the nucleus accumbens also disrupted foraging on this task, whereas disconnections between the MDNt and the nucleus accumbens had no effect. These data suggest that Serial Transmission of information among the MDNt, the prefrontal cortex, and the nucleus accumbens is required when trial-unique, short-term spatial memory is used to guide prospective search behavior. The results are discussed with respect to a distributed neural network linking limbic, thalamic, cortical, and striatal regions, which mediates executive functions of working memory.
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selective roles for hippocampal prefrontal cortical and ventral striatal circuits in radial arm maze tasks with or without a delay
The Journal of Neuroscience, 1997Co-Authors: Stan B Floresco, Jeremy K Seamans, Anthony G PhillipsAbstract:The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The two-phase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that Serial Transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on Serial Transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbic–cortical–striatal networks.
