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Neharika G Chamachi, Suman Chakrabarty
The structural basis of misfolding pathways of a cellular Prion (PrP(C)) into the toxic scrapie form (PrP(SC)) and identification of possible intermediates (e.g. PrP(*)) still eludes us. In this work, we have used a cumulative ~65µs of Replica Exchange Molecular Dynamics simulation data to construct the conformational free energy landscapes and capture the structural and thermodynamic characteristics associated with various stages of the thermal denaturation process in human Prion protein. The temperature dependent free energy surfaces consist of multiple metastable states stabilized by non-native contacts and hydrogen bonds, thus rendering the protein prone towards misfolding...
January 19, 2017: Biochemistry
Laura Cracco, Silvio Notari, Ignazio Cali, Man-Sun Sy, Shu G Chen, Mark L Cohen, Bernardino Ghetti, Brian S Appleby, Wen-Quan Zou, Byron Caughey, Jiri G Safar, Pierluigi Gambetti
In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrP(Sc)) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrP(Sc) type 2 but are associated with quite distinct phenotypes...
January 16, 2017: Scientific Reports
Luisa Gregori, Arthur Serer, Kristy L McDowell, Juraj Cervenak, David M Asher
BACKGROUND: Creutzfeldt-Jakob disease (CJD) has been accidentally transmitted by contaminated corneal transplants. Eye donors are not ordinarily tested for CJD, in part because an easy test is not available. We propose a relatively simple postmortem procedure to collect brain samples without performing full autopsy and show that a test currently marketed for veterinary diagnosis would offer an effective screening test. METHODS: We selected 6 brains from confirmed cases of human sporadic CJD and sampled each in triplicate (18 specimens), 28 control brains of individuals with non-CJD neurodegenerative diseases and 10 normal brains...
January 9, 2017: Transplantation
Daniela Meloni, Elena Bozzetta, Jan P M Langeveld, Martin H Groschup, Wilfred Goldmann, Olivier Andrèoletti, Isabelle Lantier, Lucien Van Keulen, Alex Bossers, Danilo Pitardi, Romolo Nonno, Theodoros Sklaviadis, Francesco Ingravalle, Simone Peletto, Silvia Colussi, Pier Luigi Acutis
We report the diagnostic sensitivity of 3 EU-approved rapid tests (ELISAs; 1 from IDEXX and 2 from Bio-Rad) for the detection of transmissible spongiform encephalopathy diseases in goats. Ninety-eight goat brainstem samples were tested. All the rapid tests had 100% specificity and ≥80% sensitivity, with the IDEXX test significantly more sensitive than the 2 Bio-Rad tests. All tests detected 100% of samples from goats with clinical scrapie, but missed 8% (IDEXX) to 33% (Bio-Rad SG) of samples from preclinical goats...
January 1, 2017: Journal of Veterinary Diagnostic Investigation
Muhammad Waqas, Hye-Mi Lee, Jeeyoung Kim, Glenn Telling, Jin-Ki Kim, Dae-Hwan Kim, Chongsuk Ryou
Biological effect of poly-L-arginine (PLR), the linear homopolymer comprised of L-arginine, was investigated to determine the activity of suppressing prions. PLR decreased the level of scrapie prion protein (PrP(Sc)) in cultured cells permanently infected with prions in a concentration-dependent manner. The PrP(Sc) inhibition efficacy of PLR was greater than that of another prion-suppressant poly-L-lysine (PLK) in a molecular mass-dependent fashion. The effective concentration of PLR to inhibit prions was achieved safely below the cytotoxic concentrations, and overall cytotoxicity of PLR was similar to that of PLK...
January 7, 2017: Molecular and Cellular Biochemistry
Reman Kumar Singh, Neharika G Chamachi, Suman Chakrabarty, Arnab Mukherjee
Misfolding and aggregation of prion proteins are associated with several neurodegenerative diseases. Therefore, understanding the mechanism of the misfolding process is of enormous interest in the scientific community. It has been speculated and widely discussed that the native PrPC form needs to undergo substantial unfolding to a more stable PrPC* state, which may further oligomerize into the toxic scrapie (PrPSc) form. Here we have studied the mechanism of unfolding of human prion protein (huPrP) using a set of extensive well-tempered metadynamics simulations...
December 28, 2016: Journal of Physical Chemistry. B
Saurabh Srivastava, Elizaveta Katorcha, Martin L Daus, Peter Lasch, Michael Beekes, Ilia V Baskakov
Prions or PrP(Sc) are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrP(C) The current work tests a new hypothesis that sialylation determines the fate of prions in an organism. To begin, we produced control PrP(Sc) from PrP(C) using Protein Misfolding Cyclic Amplification (PMCAb), and also generated PrP(Sc) with reduced sialylation levels using the same method but with partially desialylated PrP(C) as a substrate (dsPMCAb)...
December 20, 2016: Journal of Biological Chemistry
Qi Shi, Li-Na Chen, Yan Lv, Bao-Yun Zhang, Kang Xiao, Wei Zhou, Cao Chen, Jing Sun, Xiao-Dong Yang, Xiao-Ping Dong
PURPOSE: To analyze the proteomics patterns in the cortex regions of scrapie strains 139A and ME7 infected mice collected in the middle and terminal stages. EXPERIMENTAL DESIGN: Western Blot and immunohistochemistry methods were used to analyze the pathological changes of mice collected in the middle and terminal stages. The technique of isobaric tags for relative and absolute quantitation (iTRAQ) plus multidimensional liquid chromatography and Mass Spectropetry were used to analyze the proteomics patterns of mice in different stages...
December 19, 2016: Proteomics. Clinical Applications
Yi-An Zhan, Romany Abskharon, Yu Li, Jue Yuan, Liang Zeng, Johnny Dang, Manuel Camacho Martinez, Zerui Wang, Jacqueline Mikol, Sylvain Lehmann, Shizhong Bu, Jan Steyaert, Li Cui, Robert B Petersen, Qingzhong Kong, Gong-Xiang Wang, Alexandre Wohlkonig, Wen-Quan Zou
Prions are infectious proteins that cause a group of fatal transmissible diseases in animals and humans. The scrapie isoform (PrP(Sc)) of the cellular prion protein (PrP(C)) is the only known component of the prion. Several lines of evidence have suggested that the formation and molecular features of PrP(Sc) are associated with an abnormal unfolding/refolding process. Quiescin-sulfhydryl oxidase (QSOX) plays a role in protein folding by introducing disulfides into unfolded reduced proteins. Here we report that QSOX inhibits human prion propagation in protein misfolding cyclic amplification reactions and murine prion propagation in scrapie-infected neuroblastoma cells...
December 11, 2016: Aging
David Sanz Rubio, Óscar López-Pérez, Alvaro de Andrés Pablo, Rosa Bolea, Rosario Osta, Juan J Badiola, Pilar Zaragoza, Inmaculada Martín-Burriel, Janne M Toivonen
Scrapie is a transmissible spongiform encephalopathy (TSE), or prion disease, of sheep and goats. As no simple diagnostic tests are yet available to detect TSEs in vivo, easily accessible biomarkers could facilitate the eradication of scrapie agents from the food chain. To this end, we analysed by quantitative RT-PCR a selected set of candidate microRNAs (miRNAs) from circulating blood plasma of naturally infected, classical scrapie sheep that demonstrated clear scrapie symptoms and pathology. Significant scrapie-associated increase was repeatedly found for miR-342-3p and miR-21-5p...
December 13, 2016: Journal of General Virology
Christopher J Silva, Melissa L Erickson-Beltran, Colleen Hui, Juan José Badiola, Eric M Nicholson, Jesus Rodriguez Requena, Rosa Bolea
Scrapie is a prion (PrP(Sc)) disease of sheep. The incubation period of sheep scrapie is strongly influenced by polymorphisms at positions 136, 154, and 171 of a sheep's normal cellular prion protein (PrP(C)). Chymotrypsin was used to digest sheep recombinant PrP to identify a set of characteristic peptides [M132LGS<u>X</u>MSRPL141 (X = A or V), Y153<u>X</u>ENMY158 (X= H or R), and Y166RPVD<u>X</u>Y172 (X = H, K, Q, or R)] that could be used to detect and quantitate polymorphisms at positions 136, 154, and 171 of sheep PrP(C) or PrP(Sc)...
December 11, 2016: Analytical Chemistry
D B Adams
Unsettled knowledge as to whether scrapie transmits prenatally in sheep and goats and transmits by semen and preimplantation embryos has a potential to compromise measures for controlling, preventing and eliminating the disease. The remedy may be analysis according to a systematic review, allowing comprehensive and accessible treatment of evidence and reasoning, clarifying the issue and specifying the uncertainties. Systematic reviews have clearly formulated questions, can identify relevant studies and appraise their quality and can summarise evidence and reasoning with an explicit methodology...
2016: Open veterinary journal
Xiao -Dong Yang, Qi Shi, Jing Sun, Yan Lv, Yue Ma, Cao Chen, Kang Xiao, Wei Zhou, Xiao-Ping Dong
The abnormal mitochondrial dynamics has been reported in the brains of some neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), but limitedly described in prion disease. Dynamin-related protein 1 (Drpl) and optic atrophy protein 1 (Opa1) are two essential elements for mitochondria fission and fusion. To evaluate possible changes of mitochondria dynamics during prion infection, the situations of brain Drp1 and Opa1 of scrapie strains 139A, ME7, and S15 mice, as well as 263K-infected hamsters, were analyzed...
December 6, 2016: Journal of Molecular Neuroscience: MN
Ilaria Vanni, Sergio Migliore, Gian Mario Cosseddu, Michele Angelo Di Bari, Laura Pirisinu, Claudia D'Agostino, Geraldina Riccardi, Umberto Agrimi, Romolo Nonno
It is widely known that prion strains can mutate in response to modification of the replication environment and we have recently reported that prion mutations can occur in vitro during amplification of vole-adapted prions by Protein Misfolding Cyclic Amplification on bank vole substrate (bvPMCA). Here we exploited the high efficiency of prion replication by bvPMCA to study the in vitro propagation of natural scrapie isolates. Although in vitro vole-adapted PrPSc conformers were usually similar to the sheep counterpart, we repeatedly isolated a PrPSc mutant exclusively when starting from extremely diluted seeds of a single sheep isolate...
November 2016: PLoS Pathogens
Matthias Schmitz, Franc Llorens, Alexander Pracht, Tobias Thom, Ângela Correia, Saima Zafar, Isidre Ferrer, Inga Zerr
The identification of reliable diagnostic biomarkers in differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous two-dimensional proteomic study on cerebrospinal fluid (CSF) revealed an elevated level of an enzyme, mitochondrial malate dehydrogenase 1 (MDH1), in sporadic Creutzfeldt-Jakob disease (sCJD) patients. Here, we could demonstrate the expression of MDH1 in neurons as well as in the neuropil. Its levels are lower in sCJD brains than in control brains. An examination of CSF-MDH1 in sCJD patients by ELISA revealed a significant elevation of CSF-MDH1 levels in sCJD patients (independently from the PRNP codon 129 MV genotype or the prion protein scrapie (PrP(Sc)) type) in comparison to controls...
November 14, 2016: Aging
Jin-Kyu Choi, Ignazio Cali, Krystyna Surewicz, Qingzhong Kong, Pierluigi Gambetti, Witold K Surewicz
Recombinant C-terminally truncated prion protein PrP23-144 (which corresponds to the Y145Stop PrP variant associated with a Gerstmann-Sträussler-Scheinker-like prion disease) spontaneously forms amyloid fibrils with a parallel in-register β-sheet architecture and β-sheet core mapping to residues ∼112-139. Here we report that mice (both tga20 and wild type) inoculated with a murine (moPrP23-144) version of these fibrils develop clinical prion disease with a 100% attack rate. Remarkably, even though fibrils in the inoculum lack the entire C-terminal domain of PrP, brains of clinically sick mice accumulate longer proteinase K-resistant (PrP(res)) fragments of ∼17-32 kDa, similar to those observed in classical scrapie strains...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Karen E Marshall, Andrew Hughson, Sarah Vascellari, Suzette A Priola, Akikazu Sakudo, Takashi Onodera, Gerald S Baron
: Glycosylphosphatidylinositol (GPI) anchoring of the prion protein (PrP(C)) influences PrP(C) misfolding into the disease-associated isoform, PrP(res), as well as prion propagation and infectivity. GPI proteins are found in cholesterol- and sphingolipid-rich membrane regions called rafts. Exchanging the GPI anchor for a nonraft transmembrane sequence redirects PrP(C) away from rafts. Previous studies showed that nonraft transmembrane PrP(C) variants resist conversion to PrP(res) when transfected into scrapie-infected N2a neuroblastoma cells, likely due to segregation of transmembrane PrP(C) and GPI-anchored PrP(res) in distinct membrane environments...
January 15, 2017: Journal of Virology
Valerija Kovač, Iva Hafner-Bratkovič, Vladka Čurin Šerbec
Prion diseases are a group of fatal neurodegenerative diseases caused by scrapie form of prion protein, PrP(Sc). Prion protein (PrP) is bound to the cell via glycophosphatidylinositol (GPI) anchor. The role of GPI anchor in PrP(Sc) replication and propagation remains unclear. It has been shown that anchorless and truncated PrP accelerate the formation and propagation of prions in vivo and further increases the risk for transmission of prion diseases among species. To explain the role of anchorless forms of PrP in the development of prion diseases, we have prepared five C-terminal PrP truncated variants, determined their thermodynamic properties and analyzed the kinetics of conversion into amyloid fibrils...
December 2, 2016: Biochemical and Biophysical Research Communications
Chen Gao, Jing Wei, Bao-Yun Zhang, Qiang Shi, Cao Chen, Jing Wang, Qi Shi, Xiao-Ping Dong
MicroRNA (miRNA) is a class of non-coding endogenous small-molecule single-stranded RNA that regulates complementary mRNA through degradation or translation of the mRNA targets. Usually, miRNAs show remarkable cell and tissues specificity. Recently, alterations in a set of miRNAs in the brains of patients with certain neurodegenerative diseases, including prion diseases, have been reported. In this study, using deep sequencing technology, miRNA expression profiles in the brains of mice infected with scrapie agents 139A, ME7 and S15 at a terminal stage were comparatively analysed...
November 9, 2016: Emerging Microbes & Infections
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