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James A Carroll, Brent Race, Katie Williams, James Striebel, Bruce Chesebro
Microglial cells in the central nervous system play important roles in neurodevelopment and resistance to infection, yet microglia can become neurotoxic under some conditions. An early event during prion infection is the activation of microglia and astrocytes in the brain prior to damage or death of neurons. Previous prion disease studies using two different strategies to manipulate signaling through the microglial receptor CSF-1R reported contrary effects on survival from prion disease. However, in these studies, reduction of microglial numbers and function were variable, thus confounding interpretation of the results...
May 16, 2018: Journal of Virology
Erik J Alred, Izra Lodangco, Jennifer Gallaher, Ulrich H E Hansmann
Prion diseases are connected with self-replication and self-propagation of misfolded proteins. The rate-limiting factor is the formation of the initial seed. We have recently studied the early stages in the conversion between functional PrPC and the infectious scrapie PrPSC form, triggered by the binding of RNA. Here, we study how this process is modulated by the prion sequence. We focus on residues 129 and 178, which are connected to the hereditary neurodegenerative disease fatal familial insomnia.
April 30, 2018: ACS Omega
Jie Li, Shaoli Zhang, Sarantsetseg Erdenee, Xiuzhu Sun, Ruihua Dang, Yongzhen Huang, Chuzhao Lei, Hong Chen, Hongwei Xu, Yong Cai, Xianyong Lan
Studies of the ovine prion-related protein (testis-specific) gene (PRNT), including studies of genetic diversity, have highlighted its potential relationship to scrapie infection and economically important ovine traits. PRNT was previously reported to be highly polymorphic in Portuguese sheep. To characterize genetic polymorphisms in this gene in Asian sheep, a direct sequencing method was used to detect polymorphic loci in PRNT in 285 individual sheep from four Chinese and one Mongolian breeds. Seven SNP variants in PRNT were identified, including three novel variants (g...
April 26, 2018: Prion
Qi Shi, Jian-Le Li, Yue Ma, Li-Ping Gao, Kang Xiao, Jing Wang, Wei Zhou, Cao Chen, Yan-Jun Guo, Xiao-Ping Dong
The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected cell line SMB-S15 and its infected mice were tested. RyR2 specific Western blots revealed markedly decreased RyR2 levels both in the cells and in the brains of infected mice. Assays of the brain samples of other scrapie (agents 139A and ME7) infected mice collected at different time-points during incubation period showed time-dependent decreases of RyR2...
April 20, 2018: Prion
Alakesh Bera, Sajal Biring
Different studies indicated that the prion protein induces hybridization of complementary DNA strands. Cell culture studies showed that the scrapie isoform of prion protein remained bound with the chromosome. In present work, we used an oxazole dye, YOYO, as a reporter to quantitative characterization of the DNA condensation by prion protein. We observe that the prion protein induces greater fluorescence quenching of YOYO intercalated in DNA containing only GC bases compared to the DNA containing four bases whereas the effect of dye bound to DNA containing only AT bases is marginal...
2018: Journal of Nucleic Acids
Baaissa Babelhadj, Michele Angelo Di Bari, Laura Pirisinu, Barbara Chiappini, Semir Bechir Suheil Gaouar, Geraldina Riccardi, Stefano Marcon, Umberto Agrimi, Romolo Nonno, Gabriele Vaccari
Prions cause fatal and transmissible neurodegenerative diseases, including Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform encephalopathy (BSE). After the BSE epidemic, and the associated human infections, began in 1996 in the United Kingdom, general concerns have been raised about animal prions. We detected a prion disease in dromedary camels (Camelus dromedarius) in Algeria. Symptoms suggesting prion disease occurred in 3.1% of dromedaries brought for slaughter to Ouargla abattoir in 2015-2016...
June 17, 2018: Emerging Infectious Diseases
Naoyuki Chosa, Akira Ishisaki
Mesenchymal stem cells (MSCs) retain the ability to self-renew and differentiate into mesenchymal cells. Therefore, human MSCs are suitable candidates for use in regenerative medicine and cell therapies. Upon activation by tissue damage, MSCs contribute to tissue repair through a multitude of processes such as self-renewal, migration, and differentiation. However, loss of self-renewal and multi-lineage differentiation potential occurs at a high rate during cell doubling. Effective MSC therapies require the establishment of new techniques that preserve MSC multipotency after lengthy cell expansions...
February 2018: Japanese Dental Science Review
Soochan Kim, Sinsuk Han, Taehyun Kim, Jeehoon Nam, Yong-Sun Kim, Eun-Kyoung Choi, Mi-Yeon Kim
We previously reported that mice intracerebrally inoculated with the mouse-adapted scrapie strain ME7 have markedly diminished T zones in the spleen due to the decreased expression of CCL19 and CCL21. In addition, follicular dendritic cell networks in germinal centers were larger in ME7-infected spleens compared to uninfected spleens. As an extension of that study, we set out to determine how ME7 infection affects spleen structure and follicular helper T (Tfh) cell responses in mice. For this study, mice were intraperitoneally inoculated with brain homogenate of the ME7 inoculum and spleens were analyzed 50, 130, and 200 days after inoculation and compared with those from uninfected mice...
April 4, 2018: Prion
Thomas J Hagenaars, Marielle B Melchior, Jack J Windig, Alex Bossers, Aart Davidse, Fred G van Zijderveld
Scrapie is a transmissible spongiform encephalopathy in sheep and an example of a disease that may be controlled through breeding for disease resistance. Member states of the European Union have introduced strategies for breeding against scrapie based on the selection of genetically resistant breeding rams. An ambitious strategy adopted in The Netherlands consisted of selecting resistant rams for breeding throughout both breeding and production sectors. Mathematical modelling of the effect of a breeding program on the spreading capacity of scrapie in a national flock is needed for making assessments on how long a breeding strategy needs to be maintained to achieve disease control...
2018: PloS One
Franc Llorens, Tomás Barrio, Ângela Correia, Anna Villar-Piqué, Katrin Thüne, Peter Lange, Juan José Badiola, Matthias Schmitz, Ingolf Lachmann, Rosa Bolea, Inga Zerr
The analysis of the cerebrospinal fluid (CSF) biomarkers in patients with suspected prion diseases became a useful tool in diagnostic routine. Prion diseases can only be identified at clinical stages when the disease already spread throughout the brain and massive neuronal damage occurs. Consequently, the accuracy of CSF tests detecting non-symptomatic patients is unknown. Here, we aimed to investigate the usefulness of CSF-based diagnostic tests in pre-clinical and clinical naturally occurring scrapie. While decreased total prion protein (PrP) levels and positive PrP seeding activity were already detectable at pre-symptomatic stages, the surrogate markers of neuronal damage total tau (tau) and 14-3-3 proteins were exclusively increased at clinical stages...
March 23, 2018: Molecular Neurobiology
Kitty Schulman, Tapani Lyytikäinen
We applied scenario tree modeling to study how the genetic distribution of the sheep population in Finland and the focusing on fallen stock would influence the surveillance sensitivity of scrapie. To incorporate the unevenly distributed susceptibility into the estimation we used data from GB where the genetic distribution and scrapie occurrence have been documented in both normally slaughtered and deceased animals. Finland's sheep population is more susceptible to scrapie than the sheep population in GB and surveillance is concentrated on fallen stock...
April 1, 2018: Preventive Veterinary Medicine
Angelica Nakagawa Lima, Ronaldo Junio de Oliveira, Antônio Sérgio Kimus Braz, Maurício Garcia de Souza Costa, David Perahia, Luis Paulo Barbour Scott
There are two different prion conformations: (1) the cellular natural (PrPC ) and (2) the scrapie (PrPSc ), an infectious form that tends to aggregate under specific conditions. PrPC and PrPSc are widely different regarding secondary and tertiary structures. PrPSc contains more and longer β-strands compared to PrPC . The lack of solved PrPSc structures precludes a proper understanding of the mechanisms related to the transition between cellular and scrapie forms, as well as the aggregation process. In order to investigate the conformational transition between PrPC and PrPSc , we applied MDeNM (molecular dynamics with excited normal modes), an enhanced sampling simulation technique that has been recently developed to probe large structural changes...
March 15, 2018: European Biophysics Journal: EBJ
Maria Letizia Barreca, Nunzio Iraci, Silvia Biggi, Violetta Cecchetti, Emiliano Biasini
Prion diseases are associated with the conversion of the cellular prion protein (PrPC ), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc ) that accumulates in brain tissues of affected individuals. PrPSc is a self-catalytic protein assembly capable of recruiting native conformers of PrPC , and causing their rearrangement into new PrPSc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrPSc , and a number of compounds have shown potent anti-prion effects in experimental models...
March 7, 2018: Pathogens
Paola Sacchi, Roberto Rasero, Giuseppe Ru, Eleonora Aiassa, Silvia Colussi, Francesco Ingravalle, Simone Peletto, Maria Gabriella Perrotta, Stefano Sartore, Dominga Soglia, Pierluigi Acutis
The European Union has implemented breeding programmes to increase scrapie resistance in sheep. A similar approach can be applied also in goats since the K222 allele provides a level of resistance equivalent to that of ARR in sheep. The European Food Safety Authority stated that breeding for resistance could be offered as an option for Member States to control classical scrapie in goats. We assessed the impact of different breeding strategies on PRNP genotype frequencies using a mathematical model that describes in detail the evolution of K222 in two goat breeds, Chamois Coloured and Saanen...
March 6, 2018: Veterinary Research
M U Cinar, D A Schneider, D F Waldron, K I O'Rourke, S N White
Scrapie is a transmissible spongiform encephalopathy of sheep and goats, and scrapie eradication programs in many parts of the world rely on strong genetic resistance to classical scrapie in sheep. However, the utility of putative resistance alleles in goats has been a focus of research because goats can transmit scrapie to sheep and may serve as a scrapie reservoir. Prior work showed that disease-free survival time was significantly extended in orally inoculated goats singly heterozygous for prion amino acid substitutions S146 or K222, but average durations were only around 3 years post-inoculation...
March 2018: Veterinary Journal
David Huyben, Sofia Boqvist, Volkmar Passoth, Lena Renström, Ulrika Allard Bengtsson, Olivier Andréoletti, Anders Kiessling, Torbjörn Lundh, Ivar Vågsholm
Yeasts can be used to convert organic food wastes to protein-rich animal feed in order to recapture nutrients. However, the reuse of animal-derived waste poses a risk for the transmission of infectious prions that can cause neurodegeneration and fatality in humans and animals. The aim of this study was to investigate the ability of yeasts to reduce prion activity during the biotransformation of waste substrates-thereby becoming a biosafety hurdle in such a circular food system. During pre-screening, 30 yeast isolates were spiked with Classical Scrapie prions and incubated for 72 h in casein substrate, as a waste substitute...
February 8, 2018: Acta Veterinaria Scandinavica
Carolina Sánchez-López, Claudio O Fernández, Liliana Quintanar
The cellular prion protein (PrPC ) is a copper binding protein that undergoes post-translational modifications, such as endoproteolytic alpha cleavage, which occurs in the vicinity of the His111 Cu binding site. Alpha cleavage processing of PrPC is considered to be neuroprotective since the cleavage site is located in a region that is key to the conversion of PrPC into the infectious scrapie isoform (PrPSc ), yielding a membrane bound C1 fragment of PrPC that still contains His111. In this work, we use hPrP(111-115) fragment as a model peptide to evaluate the impact of alpha cleavage processing of PrPC in its ability to coordinate Cu(ii) ions at His111...
February 8, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Holger Wille, Jesús R Requena
PrPSc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. PrPSc is an alternatively folded variant of the cellular prion protein, PrPC , which is a regular, GPI-anchored protein that is present on the cell surface of neurons and other cell types. While the structure of PrPC is well studied, the structure of PrPSc resisted high-resolution determination due to its general insolubility and propensity to aggregate...
February 7, 2018: Pathogens
Maria Domenica Pintore, Walter Mignone, Giovanni Di Guardo, Sandro Mazzariol, Marco Ballardini, Caterina Lucia Florio, Maria Goria, Angelo Romano, Santo Caracappa, Federica Giorda, Laura Serracca, Alessandra Pautasso, Cristiana Tittarelli, Antonio Petrella, Giuseppe Lucifora, Fabio Di Nocera, Barbara Degli Uberti, Cristiano Corona, Cristina Casalone, Barbara Iulini
  We summarized the neuropathologic findings in 60 cetaceans stranded along the Italian coastline from 2002 to 2014. The following neuropathologic changes were detected in 45% (27/60) of animals: nonsuppurative meningo-encephalitides (30%, 18/60), nonspecific lesions (12%, 7/60), suppurative encephalitis (2%, 1/60), and neoplasm (2%, 1/60). No histologic lesions were found in 47% (28/60) of the specimens. Five (8%, 5/60) samples were unsuitable for analysis. Analysis with PCR detected Brucella spp., morbillivirus, and Toxoplasma gondii infection in one, six, and seven individuals, respectively...
April 2018: Journal of Wildlife Diseases
C R Seed, P E Hewitt, R Y Dodd, F Houston, L Cervenakova
Transmissible spongiform encephalopathies (TSEs) are untreatable, fatal neurologic diseases affecting mammals. Human disease forms include sporadic, familial and acquired Creutzfeldt-Jakob disease (CJD). While sporadic CJD (sCJD) has been recognized for near on 100 years, variant CJD (vCJD) was first reported in 1996 and is the result of food-borne transmission of the prion of bovine spongiform encephalopathy (BSE, 'mad cow disease'). Currently, 230 vCJD cases have been reported in 12 countries, the majority in the UK (178) and France (27)...
April 2018: Vox Sanguinis
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