scholarly journals Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

2013 ◽  
Vol 94 (6) ◽  
pp. 1435-1440 ◽  
Author(s):  
Sophie Halliez ◽  
Nathalie Chesnais ◽  
Giovanna Mallucci ◽  
Marthe Vilotte ◽  
Christelle Langevin ◽  
...  
Keyword(s):  
Nervous System ◽  
Schwann Cells ◽  
Prion Protein ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
The Central Nervous System ◽  
Myelinated Nerves ◽  
Pathogenic Agents ◽  
The Brain

In naturally acquired transmissible spongiform encephalopathies, the pathogenic agents or prions spread from the sites of initial peripheral uptake or replication to the brain where they cause progressive and fatal neurodegeneration. Routing via the peripheral nervous system is considered to be one of the main pathways to the central nervous system. Replication of prions in Schwann cells is viewed as a potentially important mechanism for efficient prion spread along nerves. Here we used a Cre-loxP mouse transgenetic approach to disrupt host-encoded prion protein (PrPC) specifically in myelinating Schwann cells. Despite the use of infection routes targeting highly myelinated nerves, there was no alteration in mouse prion pathogenesis, suggesting that conversion-dependent, centripetal spread of prions does not crucially rely on PrPC expressed by myelinating Schwann cells.

scholarly journals Prion Diseases and the Gastrointestinal Tract

2006 ◽  
Vol 20 (1) ◽  
pp. 18-24 ◽  
Author(s):  
Gwynivere A Davies ◽  
Adam R Bryant ◽  
John D Reynolds ◽  
Frank R Jirik ◽  
Keith A Sharkey
Keyword(s):  
Nervous System ◽  
Dendritic Cells ◽  
Enteric Nervous System ◽  
Prion Protein ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Gi Tract ◽  
Spongiform Encephalopathies ◽  
The Brain

The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Alhough they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPscpropagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer’s patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPscin the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

scholarly journals Abnormal prion protein in genetically resistant sheep from a scrapie-infected flock

2004 ◽  
Vol 85 (11) ◽  
pp. 3483-3486 ◽  
Author(s):  
J.-Y. Madec ◽  
S. Simon ◽  
S. Lezmi ◽  
A. Bencsik ◽  
J. Grassi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Sandwich Elisa ◽  
Protein A ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Motor Nucleus ◽  
Entry Site ◽  
Spongiform Encephalopathies ◽  
Dorsal Motor Nucleus ◽  
The Brain

The central molecular event in transmissible spongiform encephalopathies, such as scrapie in sheep, is the accumulation in tissues of an abnormal isoform of the cellular prion protein. A previous investigation of 26 sheep showed that the accumulation of PrPres in brain correlated more with the prnp genotype than with the severity of the clinical disease. Here, the ability of a sandwich ELISA to detect PrPres distribution in the brain was demonstrated. Immunohistochemistry also strongly supported the hypothesis that the dorsal motor nucleus of the vagus nerve is the possible entry site in the brain for the scrapie agent. Remarkably, three asymptomatic (or possibly asymptomatic for scrapie) sheep carrying an allele known to be associated with clinical scrapie resistance (ARR), which were negative for the detection of PrPres by Western blotting and immunohistochemistry, were positive for the presence of PrPres by ELISA, raising the possibility of carriers resistant to the disease and possibly contributing to the persistence of scrapie in certain flocks.

scholarly journals Characterization of the role of dendritic cells in prion transfer to primary neurons

2010 ◽  
Vol 431 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Christelle Langevin ◽  
Karine Gousset ◽  
Maddalena Costanzo ◽  
Odile Richard-Le Goff ◽  
Chiara Zurzolo
Keyword(s):  
Nervous System ◽  
Dendritic Cells ◽  
Prion Protein ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Cell Contact ◽  
Neuronal Cultures ◽  
Lymphoid Tissues ◽  
Spongiform Encephalopathies

TSEs (transmissible spongiform encephalopathies) are neurodegenerative diseases caused by pathogenic isoforms (PrPSc) of the host-encoded PrPc (cellular prion protein). After consumption of contaminated food, PrPSc deposits rapidly accumulate in lymphoid tissues before invasion of the CNS (central nervous system). However, the mechanisms of prion spreading from the periphery to the nervous system are still unclear. In the present study, we investigated the role of DCs (dendritic cells) in the spreading of prion infection to neuronal cells. First, we determined that BMDCs (bone-marrow-derived DCs) rapidly uptake PrPSc after exposure to infected brain homogenate. Next, we observed a progressive catabolism of the internalized prion aggregates. Similar experiments performed with BMDCs isolated from KO (knockout) mice or mice overexpressing PrP (tga20) indicate that both PrPSc uptake and catabolism are independent of PrPc expression in these cells. Finally, using co-cultures of prion-loaded BMDCs and cerebellar neurons, we characterized the transfer of the prion protein and the resulting infection of the neuronal cultures. Interestingly, the transfer of PrPSc was triggered by direct cell–cell contact. As a consequence, BMDCs retained the prion protein when cultured alone, and no transfer to the recipient neurons was observed when a filter separated the two cultures or when neurons were exposed to the BMDC-conditioned medium. Additionally, fixed BMDCs also failed to transfer prion infectivity to neurons, suggesting an active transport of prion aggregates, in accordance with a role of TNTs (tunnelling nanotubes) observed in the co-cultures.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

scholarly journals The Prion Protein Octarepeat Domain Forms Transient β-sheet Structures Upon Residue-Specific Cu(II) and Zn(II) Binding

2021 ◽  
Author(s):  
Maciej Gielnik ◽  
Aneta Szymanska ◽  
Xiaolin Dong ◽  
Jyri Jarvet ◽  
Zeljko M. Svedruzic ◽  
...  
Keyword(s):  
Metal Ions ◽  
Prion Protein ◽  
Metal Binding ◽  
Cd Spectroscopy ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Amyloid Formation ◽  
Spectroscopy Data ◽  
Spongiform Encephalopathies ◽  
Β Sheet

Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in the protein misfolding, and metal imbalance may be part of TSE pathologies. PrPC is a combined Cu(II) and Zn(II) metal binding protein, where the main metal binding site is located in the octarepeat (OR) region. Here, we used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Upon metal binding, the OR region seems to adopt a transient antiparallel β-sheet hairpin structure. Fluorescence spectroscopy data indicates that under neutral conditions, the OR region can bind both Cu(II) and Zn(II) ions, whereas under acidic conditions it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of both metal ions to the OR region results in formation of β-hairpin structures. As formation of β-sheet structures is a first step towards amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSEs.

scholarly journals Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maciej Gielnik ◽  
Michał Taube ◽  
Lilia Zhukova ◽  
Igor Zhukov ◽  
Sebastian K. T. S. Wärmländer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Metal Ion ◽  
Structural Transition ◽  
Cellular Prion Protein ◽  
Zinc Homeostasis ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Structural Conversion ◽  
Protein Size ◽  
Dynamics Simulations

AbstractThe cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrPC binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrPC and Zn(II) ions. Binding of a single Zn(II) ion to the PrPC N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal α-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrPC can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrPC.

scholarly journals Do Bovine Lymphocytes Express a Peculiar Prion Protein?

2002 ◽  
Vol 9 (4) ◽  
pp. 245-252 ◽  
Author(s):  
France Mélot ◽  
Caroline Thielen ◽  
Thouraya Labiet ◽  
Sabine Eisher ◽  
Olivier Jolois ◽  
...  
Keyword(s):  
Prion Protein ◽  
Immune Cells ◽  
Surface Protein ◽  
In Vitro Study ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Lymphoid Tissues ◽  
Spongiform Encephalopathies ◽  
Bovine Lymphocytes

The cellular prion protein (PrPc) is a glycolipid-anchored cell surface protein that usually exhibits three glycosylation states. Its post-translationally modified isoform, PrPsc, is involved in the pathogenesis of various transmissible spongiform encephalopathies (TSEs). In bovine species, BSE infectivity appears to be restricted to the central nervous system; few or no detectable infectivity is found in lymphoid tissues in contrast to scrapie or variant CJD. Since expression of PrPc is a prerequisite for prion replication, we have investigated PrPc expression by bovine immune cells. Lymphocytes from blood and five different lymph organs were isolated from the same animal to assess intra- and interindividual variability of PrPc expression, considering six individuals. As shown by flow cytometry, this expression is absent or weak on granulocytes but is measurable on monocytes, B and T cells from blood and lymph organs. The activation of the bovine cells produces an upregulation of PrPc. The results of our in vitro study of PrPc biosynthesis are consistent with previous studies in other species. Interestingly, western blotting experiments showed only one form of the protein, the diglycosylated band. We propose that the glycosylation state could explain the lack of infectivity of the bovine immune cells.

Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein

2006 ◽  
Vol 7 (1-2) ◽  
pp. 97-105 ◽  
Author(s):  
Scott P. Leach ◽  
M. D. Salman ◽  
Dwayne Hamar
Keyword(s):  
Trace Elements ◽  
Prion Protein ◽  
Copper Ions ◽  
Prion Diseases ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Copper Binding ◽  
Spongiform Encephalopathies ◽  
Copper Manganese ◽  
The Brain

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.

scholarly journals A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
N. C. Ferreira ◽  
L. M. Ascari ◽  
A. G. Hughson ◽  
G. R. Cavalheiro ◽  
C. F. Góes ◽  
...  
Keyword(s):  
Cell Surface ◽  
Real Time ◽  
Prion Protein ◽  
Molecular Mechanisms ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Globular Domain ◽  
Mrna Levels ◽  
Spongiform Encephalopathies

ABSTRACTThe search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrPC) conversion into protease-resistant forms (protease-resistant PrP [PrPRes] or the scrapie form of PrP [PrPSc]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identifiedin vitroto be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrPCmRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP23–231) as the substrate and PrPScseeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP90–231), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrPCglobular domain. J8 also reduced the fibrillation of mouse rPrP23–231seeded within vitro-produced fibrils. Furthermore, most of the compounds decreased the amount of PrPCon the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrPCcontent on the cell surface.

scholarly journals Prion protein β2–α2 loop conformational landscape

2017 ◽  
Vol 114 (36) ◽  
pp. 9617-9622 ◽  
Author(s):  
Enrico Caldarulo ◽  
Alessandro Barducci ◽  
Kurt Wüthrich ◽  
Michele Parrinello
Keyword(s):  
Prion Protein ◽  
Mammalian Species ◽  
Wild Type Mouse ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Surface ◽  
Spongiform Encephalopathies ◽  
New Information ◽  
Amyloid Aggregates ◽  
Wide Range

In transmissible spongiform encephalopathies (TSEs), which are lethal neurodegenerative diseases that affect humans and a wide range of other mammalian species, the normal “cellular” prion protein (PrPC) is transformed into amyloid aggregates representing the “scrapie form” of the protein (PrPSc). Continued research on this system is of keen interest, since new information on the physiological function of PrPC in healthy organisms is emerging, as well as new data on the mechanism of the transformation of PrPC to PrPSc. In this paper we used two different approaches: a combination of the well-tempered ensemble (WTE) and parallel tempering (PT) schemes and metadynamics (MetaD) to characterize the conformational free-energy surface of PrPC. The focus of the data analysis was on an 11-residue polypeptide segment in mouse PrPC(121–231) that includes the β2–α2 loop of residues 167–170, for which a correlation between structure and susceptibility to prion disease has previously been described. This study includes wild-type mouse PrPC and a variant with the single-residue replacement Y169A. The resulting detailed conformational landscapes complement in an integrative manner the available experimental data on PrPC, providing quantitative insights into the nature of the structural transition-related function of the β2–α2 loop.

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