scholarly journals Mechanisms of Cell Death in the Transmissible Spongiform Encephalopathies

10.5772/27985 ◽  
2012 ◽  
Author(s):  
Fiona Lane ◽  
James Alibhai ◽  
Jean C. ◽  
Andrew C.
Keyword(s):  
Cell Death ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies

scholarly journals The Prion Protein and Its Paralogue Doppel Affect Calcium Signaling in Chinese Hamster Ovary Cells

2005 ◽  
Vol 16 (6) ◽  
pp. 2799-2808 ◽  
Author(s):  
Marisa Brini ◽  
Manuela Miuzzo ◽  
Nicola Pierobon ◽  
Alessandro Negro ◽  
Maria Catia Sorgato
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Prion Protein ◽  
Neuronal Excitability ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Ovary Cells ◽  
Cell Death Pathways

The function of the prion protein (PrPc), implicated in transmissible spongiform encephalopathies (TSEs), is largely unknown. We examined the possible influence of PrPc on Ca2+ homeostasis, by analyzing local Ca2+ fluctuations in cells transfected with PrPc and Ca2+-sensitive aequorin chimeras targeted to defined subcellular compartments. In agonist-stimulated cells, the presence of PrPc sharply increases the Ca2+ concentration of subplasma membrane Ca2+ domains, a feature that may explain the impairment of Ca2+-dependent neuronal excitability observed in TSEs. PrPc also limits Ca2+ release from the endoplasmic reticulum and Ca2+ uptake by mitochondria, thus rendering unlikely the triggering of cell death pathways. Instead, cells expressing Doppel, a PrPc paralogue, display opposite effects, which, however, are abolished by the coexpression of PrPc. These findings are consistent with the functional interplay and antagonistic role attributed to the proteins, whereby PrPc protects, and Doppel sensitizes, cells toward stress conditions.

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 Effect of Scrapie Prion Infection in Ovine Bone Marrow-Derived Mesenchymal Stem Cells and Ovine Mesenchymal Stem Cell-Derived Neurons

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1137
Author(s):  
Laura García-Mendívil ◽  
Diego R. Mediano ◽  
Adelaida Hernaiz ◽  
David Sanz-Rubio ◽  
Francisco J. Vázquez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Post Inoculation ◽  
Spongiform Encephalopathies ◽  
Prion Infection ◽  
Over Time

Scrapie is a prion disease affecting sheep and goats and it is considered a prototype of transmissible spongiform encephalopathies (TSEs). Mesenchymal stem cells (MSCs) have been proposed as candidates for developing in vitro models of prion diseases. Murine MSCs are able to propagate prions after previous mouse-adaptation of prion strains and, although ovine MSCs express the cellular prion protein (PrPC), their susceptibility to prion infection has never been investigated. Here, we analyze the potential of ovine bone marrow-derived MSCs (oBM-MSCs), in growth and neurogenic conditions, to be infected by natural scrapie and propagate prion particles (PrPSc) in vitro, as well as the effect of this infection on cell viability and proliferation. Cultures were kept for 48–72 h in contact with homogenates of central nervous system (CNS) samples from scrapie or control sheep. In growth conditions, oBM-MSCs initially maintained detectable levels of PrPSc post-inoculation, as determined by Western blotting and ELISA. However, the PrPSc signal weakened and was lost over time. oBM-MSCs infected with scrapie displayed lower cell doubling and higher doubling times than those infected with control inocula. On the other hand, in neurogenic conditions, oBM-MSCs not only maintained detectable levels of PrPSc post-inoculation, as determined by ELISA, but this PrPSc signal also increased progressively over time. Finally, inoculation with CNS extracts seems to induce the proliferation of oBM-MSCs in both growth and neurogenic conditions. Our results suggest that oBM-MSCs respond to prion infection by decreasing their proliferation capacity and thus might not be permissive to prion replication, whereas ovine MSC-derived neuron-like cells seem to maintain and replicate PrPSc.

scholarly journals Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

2021 ◽  
Vol 15 (1) ◽  
pp. 193-196
Author(s):  
Máximo Sanz-Hernández ◽  
Alfonso De Simone
Keyword(s):  
Prion Protein ◽  
Nmr Assignments ◽  
Chemical Shifts ◽  
Prion Diseases ◽  
Random Coil ◽  
Transmissible Spongiform Encephalopathies ◽  
Globular Domain ◽  
Structural Elements ◽  
Spongiform Encephalopathies ◽  
Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

scholarly journals Efficient Conversion of Normal Prion Protein (PrP) by Abnormal Hamster PrP Is Determined by Homology at Amino Acid Residue 155

2001 ◽  
Vol 75 (10) ◽  
pp. 4673-4680 ◽  
Author(s):  
Suzette A. Priola ◽  
Joëlle Chabry ◽  
Kaman Chan
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Amino Acid Residue ◽  
Animal Species ◽  
Alpha Helix ◽  
Proteinase K ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
A Cell ◽  
Resistant Product

ABSTRACT In the transmissible spongiform encephalopathies, disease is closely associated with the conversion of the normal proteinase K-sensitive host prion protein (PrP-sen) to the abnormal proteinase K-resistant form (PrP-res). Amino acid sequence homology between PrP-res and PrP-sen is important in the formation of new PrP-res and thus in the efficient transmission of infectivity across species barriers. It was previously shown that the generation of mouse PrP-res was strongly influenced by homology between PrP-sen and PrP-res at amino acid residue 138, a residue located in a region of loop structure common to PrP molecules from many different species. In order to determine if homology at residue 138 also affected the formation of PrP-res in a different animal species, we assayed the ability of hamster PrP-res to convert a panel of recombinant PrP-sen molecules to protease-resistant PrP in a cell-free conversion system. Homology at amino acid residue 138 was not critical for the formation of protease-resistant hamster PrP. Rather, homology between PrP-sen and hamster PrP-res at amino acid residue 155 determined the efficiency of formation of a protease-resistant product induced by hamster PrP-res. Structurally, residue 155 resides in a turn at the end of the first alpha helix in hamster PrP-sen; this feature is not present in mouse PrP-sen. Thus, our data suggest that PrP-res molecules isolated from scrapie-infected brains of different animal species have different PrP-sen structural requirements for the efficient formation of protease-resistant PrP.

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