Prion processing: a double-edged sword?

2012 ◽  
Vol 40 (4) ◽  
pp. 735-738 ◽  
Author(s):  
Hilary E.M. McMahon
Keyword(s):  
Prion Protein ◽  
Cellular Prion Protein ◽  
Conversion Process ◽  
Oxygen Species ◽  
Amino Acid Residues ◽  
Prion Infection ◽  
C And N ◽  
The Subject ◽  
Prion Conversion ◽  
Disease Specific

The events leading to the degradation of the endogenous PrPC (normal cellular prion protein) have been the subject of numerous studies. Two cleavage processes, α-cleavage and β-cleavage, are responsible for the main C- and N-terminal fragments produced from PrPC. Both cleavage processes occur within the N-terminus of PrPC, a region that is significant in terms of function. α-Cleavage, an enzymatic event that occurs at amino acid residues 110 and 111 on PrPC, interferes with the conversion of PrPC into the prion disease-associated isoform, PrPSc (abnormal disease-specific conformation of prion protein). This processing is seen as a positive event in terms of disease development. The study of β-cleavage has taken some surprising turns. β-Cleavage is brought about by ROS (reactive oxygen species). The C-terminal fragment produced, C2, may provide the seed for the abnormal conversion process, as it resembles in size the fragments isolated from prion-infected brains. There is, however, strong evidence that β-cleavage provides an essential process to reduce oxidative stress. β-Cleavage may act as a double-edged sword. By β-cleavage, PrPC may try to balance the ROS levels produced during prion infection, but the C2 produced may provide a PrPSc seed that maintains the prion conversion process.

scholarly journals Endogenous Brain Lipids Inhibit Prion Amyloid Formation In Vitro

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Clare E. Hoover ◽  
Kristen A. Davenport ◽  
Davin M. Henderson ◽  
Mark D. Zabel ◽  
Edward A. Hoover
Keyword(s):  
Real Time ◽  
Lipid Rafts ◽  
Prion Protein ◽  
Polar Lipid ◽  
Cellular Prion Protein ◽  
Conversion Process ◽  
Amyloid Formation ◽  
Inhibitory Function ◽  
Prion Conversion

ABSTRACT The normal cellular prion protein (PrPC) resides in detergent-resistant outer membrane lipid rafts in which conversion to the pathogenic misfolded form is believed to occur. Once misfolding occurs, the pathogenic isoform polymerizes into highly stable amyloid fibrils. In vitro assays have demonstrated an intimate association between prion conversion and lipids, specifically phosphatidylethanolamine, which is a critical cofactor in the formation of synthetic infectious prions. In the current work, we demonstrate an alternative inhibitory function of lipids in the prion conversion process as assessed in vitro by real-time quaking-induced conversion (RT-QuIC). Using an alcohol-based extraction technique, we removed the lipid content from chronic wasting disease (CWD)-infected white-tailed deer brain homogenates and found that lipid extraction enabled RT-QuIC detection of CWD prions in a 2-log10-greater concentration of brain sample. Conversely, addition of brain-derived lipid extracts to CWD prion brain or lymph node samples inhibited amyloid formation in a dose-dependent manner. Subsequent lipid analysis demonstrated that this inhibitory function was restricted to the polar lipid fraction in brain. We further investigated three phospholipids commonly found in lipid membranes, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol, and found all three similarly inhibited RT-QuIC. These results demonstrating polar-lipid, and specifically phospholipid, inhibition of prion-seeded amyloid formation highlight the diverse roles lipid constituents may play in the prion conversion process. IMPORTANCE Prion conversion is likely influenced by lipid interactions, given the location of normal prion protein (PrPC) in lipid rafts and lipid cofactors generating infectious prions in in vitro models. Here, we use real-time quaking-induced conversion (RT-QuIC) to demonstrate that endogenous brain polar lipids can inhibit prion-seeded amyloid formation, suggesting that prion conversion is guided by an environment of proconversion and anticonversion lipids. These experiments also highlight the applicability of RT-QuIC to identify potential therapeutic inhibitors of prion conversion.

scholarly journals Fibrinogen-cellular prion protein complex formation on astrocytes

2020 ◽  
Vol 124 (2) ◽  
pp. 536-543 ◽  
Author(s):  
Mariam Charkviani ◽  
Nino Muradashvili ◽  
Nurul Sulimai ◽  
David Lominadze
Keyword(s):  
Prion Protein ◽  
Cellular Prion Protein ◽  
No Production ◽  
Oxygen Species ◽  
Receptor Kinase ◽  
Astrocyte Activation ◽  
Triggering Mechanism ◽  
Protein Complex Formation ◽  
Tyrosine Receptor Kinase ◽  
First Time

For the first time we showed that fibrinogen (Fg) can associate with cellular prion protein (PrPC) on the surface of cultured mouse brain astrocytes. At high levels, Fg causes upregulation of astrocyte PrPC and astrocyte activation accompanied with overexpression of tyrosine receptor kinase B (TrkB), which results in nitric oxide (NO) production and generation of reactive oxygen species (ROS). Fg/PrPC interaction can be a triggering mechanism for TrkB-NO-ROS axis activation and the resultant astrocyte-mediated neurodegeneration.

scholarly journals Small-Ruminant Lentivirus Enhances PrPSc Accumulation in Cultured Sheep Microglial Cells

2008 ◽  
Vol 82 (20) ◽  
pp. 9839-9847 ◽  
Author(s):  
James B. Stanton ◽  
Donald P. Knowles ◽  
Katherine I. O'Rourke ◽  
Lynn M. Herrmann-Hoesing ◽  
Bruce A. Mathison ◽  
...  
Keyword(s):  
Cell Line ◽  
Prion Protein ◽  
Small Ruminant ◽  
Cellular Prion Protein ◽  
Primary Cell ◽  
Microglial Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Primary Microglia ◽  
Prion Conversion ◽  
Sheep Scrapie

ABSTRACT Sheep scrapie is the prototypical transmissible spongiform encephalopathy (prion disease), which has a fundamental pathogenesis involving conversion of normal cellular prion protein (PrPC [C superscript stands for cellular]) to disease-associated prion protein (PrPSc [Sc superscript stands for sheep scrapie]). Sheep microglial cell cultures, derived from a prnp 136VV/171QQ near-term fetal brain, were developed to study sheep scrapie in the natural host and to investigate potential cofactors in the prion conversion process. Two culture systems, a primary cell culture and a cell line transformed with the large T antigen of simian virus 40, were developed, and both were identified as microglial in origin as indicated by expression of several microglial phenotype markers. Following exposure to PrPSc, sheep microglial cells demonstrated relatively low levels (transformed cell line) to high levels (primary cell line) of PrPSc accumulation over time. The accumulated PrPSc demonstrated protease resistance, an inferred beta-sheet conformation (as determined by a commercial enzyme-linked immunosorbent assay), specific inhibition by anti-PrP antibodies, and was transmissible in a dose-dependent manner. Primary microglia coinfected with a small-ruminant lentivirus (caprine arthritis encephalitis virus-Cork strain) and PrPSc demonstrated an approximately twofold increase in PrPSc accumulation compared to that of primary microglia infected with PrPSc alone. The results demonstrate the in vitro utility of PrPSc-permissive sheep microglial cells in investigating the biology of natural prion diseases and show that small-ruminant lentiviruses enhance prion conversion in cultured sheep microglia.

scholarly journals The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

2020 ◽  
Author(s):  
Elena De Cecco ◽  
Luigi Celauro ◽  
Silvia Vanni ◽  
Micaela Grandolfo ◽  
Adriano Aguzzi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Brain Diseases ◽  
Gene Encoding ◽  
Prion Propagation ◽  
Prion Conversion ◽  
Tau Fibrils

AbstractTauopathies are prevalent, invariably fatal brain diseases for which no cure is available. Tauopathies progressively affect the brain through cell-to-cell transfer of tau protein amyloids, yet the spreading mechanisms are unknown. Here we show that the cellular prion protein (PrPC) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, we found that tau amyloids bind to PrPC; internalization of tau fibrils was reduced in isogenic cells devoid of the gene encoding PrPC. Antibodies against N-proximal epitopes of PrPC impaired the binding of tau amyloids and decreased their uptake. Surprisingly, exposure of chronically prion-infected cells to tau amyloids reduced the accumulation of aggregated prion protein; this effect lasted for more than 72 hours after amyloid removal. These results point to bidirectional interactions between the two proteins: whilst PrPC mediates the entrance of tau fibrils in cells, PrPSc buildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.

scholarly journals Incomplete glycosylation during prion infection unmasks a prion protein epitope that facilitates prion detection and strain discrimination

2020 ◽  
Vol 295 (30) ◽  
pp. 10420-10433
Author(s):  
Hae-Eun Kang ◽  
Jifeng Bian ◽  
Sarah J. Kane ◽  
Sehun Kim ◽  
Vanessa Selwyn ◽  
...  
Keyword(s):  
Prion Protein ◽  
Structural Instability ◽  
Cellular Prion Protein ◽  
Wasting Disease ◽  
Prion Infection ◽  
Antibody Recognition ◽  
Causative Factors ◽  
Consistent Feature ◽  
Scrapie Strains ◽  
Conformational Conversion

The causative factors underlying conformational conversion of cellular prion protein (PrPC) into its infectious counterpart (PrPSc) during prion infection remain undetermined, in part because of a lack of monoclonal antibodies (mAbs) that can distinguish these conformational isoforms. Here we show that the anti-PrP mAb PRC7 recognizes an epitope that is shielded from detection when glycans are attached to Asn-196. We observed that whereas PrPC is predisposed to full glycosylation and is therefore refractory to PRC7 detection, prion infection leads to diminished PrPSc glycosylation at Asn-196, resulting in an unshielded PRC7 epitope that is amenable to mAb recognition upon renaturation. Detection of PRC7-reactive PrPSc in experimental and natural infections with various mouse-adapted scrapie strains and with prions causing deer and elk chronic wasting disease and transmissible mink encephalopathy uncovered that incomplete PrPSc glycosylation is a consistent feature of prion pathogenesis. We also show that interrogating the conformational properties of the PRC7 epitope affords a direct means of distinguishing different prion strains. Because the specificity of our approach for prion detection and strain discrimination relies on the extent to which N-linked glycosylation shields or unshields PrP epitopes from antibody recognition, it dispenses with the requirement for additional standard manipulations to distinguish PrPSc from PrPC, including evaluation of protease resistance. Our findings not only highlight an innovative and facile strategy for prion detection and strain differentiation, but are also consistent with a mechanism of prion replication in which structural instability of incompletely glycosylated PrP contributes to the conformational conversion of PrPC to PrPSc.

scholarly journals Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

2020 ◽  
Vol 21 (19) ◽  
pp. 7260
Author(s):  
Keiji Uchiyama ◽  
Hironori Miyata ◽  
Yoshitaka Yamaguchi ◽  
Morikazu Imamura ◽  
Mariya Okazaki ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Dependent Manner ◽  
Prion Infection ◽  
Amplification Assay ◽  
The Brain ◽  
Strain Dependent

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.

Cellular prion protein protects against reactive-oxygen-species-induced DNA damage

2007 ◽  
Vol 43 (6) ◽  
pp. 959-967 ◽  
Author(s):  
Nicole T. Watt ◽  
Michael N. Routledge ◽  
Christopher P. Wild ◽  
Nigel M. Hooper
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Prion Protein ◽  
Reactive Oxygen ◽  
Cellular Prion Protein ◽  
Oxygen Species

scholarly journals Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review

2019 ◽  
Vol 20 (14) ◽  
pp. 3606 ◽  
Author(s):  
Livia Bernardi ◽  
Amalia C. Bruni
Keyword(s):  
Prion Protein ◽  
Point Mutations ◽  
Prnp Gene ◽  
Cellular Prion Protein ◽  
Physical Interaction ◽  
Pathogenic Mechanisms ◽  
Terminal Domain ◽  
C And N ◽  
Clinical Pictures ◽  
Inherited Mutations

Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt–Jacob disease (CJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).

Developmental influence of the cellular prion protein on the gene expression profile in mouse hippocampus

2011 ◽  
Vol 43 (12) ◽  
pp. 711-725 ◽  
Author(s):  
Stefano Benvegnù ◽  
Paola Roncaglia ◽  
Federica Agostini ◽  
Cristina Casalone ◽  
Cristiano Corona ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Prion Protein ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Prion Diseases ◽  
Physiological Role ◽  
Nervous System Development ◽  
Cellular Prion Protein ◽  
Prion Infection

The conversion of the cellular prion protein (PrPC) to an abnormal and protease-resistant isoform is the key event in prion diseases. Mice lacking PrPC are resistant to prion infection, and downregulation of PrPC during prion infection prevents neuronal loss and the progression to clinical disease. These results are suggestive of the potential beneficial effect of silencing PrPC during prion diseases. However, the silencing of a protein that is widely expressed throughout the central nervous system could be detrimental to brain homeostasis. The physiological role of PrPC remains still unclear, but several putative functions (e.g., neuronal development and maintenance) have been proposed. To assess the influence of PrPC on gene expression profile in the mouse brain, we undertook a microarray analysis by using RNA isolated from the hippocampus at two different developmental stages: newborn (4.5-day-old) and adult (3-mo-old) mice, both from wild-type and Prnp0/0 animals. Comparing the different datasets allowed us to identify “commonly” co-regulated genes and “uniquely” deregulated genes during postnatal development. The absence of PrPC affected several biological pathways, the most representative being cell signaling, cell-cell communication and transduction processes, calcium homeostasis, nervous system development, synaptic transmission, and cell adhesion. However, there was only a moderate alteration of the gene expression profile in our animal models. PrPC deficiency did not lead to a dramatic alteration of gene expression profile and produced moderately altered gene expression levels from young to adult animals. Thus, our results may provide additional support to silencing endogenous PrPC levels as therapeutic approach to prion diseases.

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