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.

scholarly journals Characterization of four new monoclonal antibodies against the distal N-terminal region of PrPc

2014 ◽  
Author(s):  
Alessandro Didonna ◽  
Anja Colja Venturini ◽  
Katrina Hartman ◽  
Tanja Vranac ◽  
Vladka Curin Serbec ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Prion Protein ◽  
Biochemical Characterization ◽  
Prion Diseases ◽  
Physiological Role ◽  
Prion Infection ◽  
Promising Tool ◽  
C Terminus ◽  
N Terminus

Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. They are characterized by the accumulation in the central nervous system of a pathological form of the host-encoded prion protein (PrPC). The prion protein is a membrane glycoprotein that consists of two domains: a globular, structured C-terminus and an unstructured N-terminus. The N-terminal part of the protein is involved in different functions in both health and disease. In the present work we discuss the production and biochemical characterization of a panel of four monoclonal antibodies (mAbs) against the distal N-terminus of PrPC using a well-established methodology based on the immunization of Prnp0/0 mice. Additionally, we show their ability to block prion (PrPSc) replication at nanomolar concentrations in a cell culture model of prion infection. These mAbs represent a promising tool for prion diagnostics and for studying the physiological role of the N-terminal domain of PrPC.

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.

scholarly journals Gene Expression Profile in Prion Protein-Deficient Fibroblasts in Culture

2000 ◽  
Vol 157 (1) ◽  
pp. 59-68 ◽  
Author(s):  
Jun-ichi Satoh ◽  
Yasuo Kuroda ◽  
Shigeru Katamine
Keyword(s):  
Gene Expression ◽  
Prion Protein ◽  
Gene Expression Profile ◽  
Expression Profile

scholarly journals Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction

2020 ◽  
Vol 21 (19) ◽  
pp. 7058
Author(s):  
Hajar Miranzadeh Mahabadi ◽  
Changiz Taghibiglou
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Physiological Role ◽  
Cellular Prion Protein ◽  
Interacting Protein ◽  
Intrinsically Disordered ◽  
Outer Leaflet ◽  
Protein Partners ◽  
Wide Range ◽  
The Central Nervous System

Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.

scholarly journals Reactive Oxygen Species-mediated β-Cleavage of the Prion Protein in the Cellular Response to Oxidative Stress

2005 ◽  
Vol 280 (43) ◽  
pp. 35914-35921 ◽  
Author(s):  
Nicole T. Watt ◽  
David R. Taylor ◽  
Andrew Gillott ◽  
Daniel A. Thomas ◽  
W. Sumudhu S. Perera ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Prion Protein ◽  
Cellular Response ◽  
Prion Diseases ◽  
Physiological Role ◽  
Reactive Oxygen ◽  
Cellular Prion Protein ◽  
Critical Event ◽  
Oxygen Species

The cellular prion protein (PrPC) is critical for the development of prion diseases. However, the physiological role of PrPC is less clear, although a role in the cellular resistance to oxidative stress has been proposed. PrPC is cleaved at the end of the copper-binding octapeptide repeats through the action of reactive oxygen species (ROS), a process termed β-cleavage. Here we show that ROS-mediated β-cleavage of cell surface PrPC occurs within minutes and was inhibited by the hydroxyl radical quencher dimethyl sulfoxide and by an antibody against the octapeptide repeats. A construct of PrP lacking the octapeptide repeats, PrPΔoct, failed to undergo ROS-mediated β-cleavage, as did two mutant forms of PrP, PG14 and A116V, associated with human prion diseases. As compared with cells expressing wild type PrP, when challenged with H2O2 and Cu2+, cells expressing PrPΔoct, PG14, or A116V had reduced viability and glutathione peroxidase activity and increased intracellular free radicals. Thus, lack of ROS-mediated β-cleavage of PrP correlated with the sensitivity of the cells to oxidative stress. These data indicate that the β-cleavage of PrPC is an early and critical event in the mechanism by which PrP protects cells against oxidative stress.

P3-360 Analysis of gene expression profile of prion protein-deficient neuronal cell line from Zürich I mice

2004 ◽  
Vol 25 ◽  
pp. S458
Author(s):  
Boe-Hyun Kim ◽  
Seung-Il Choi ◽  
Jae-Il Kim ◽  
Richard I. Carp ◽  
Yong-Sun Kim
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Prion Protein ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Neuronal Cell ◽  
Neuronal Cell Line

scholarly journals Characterization of four new monoclonal antibodies against the distal N-terminal region of PrPc

2014 ◽  
Author(s):  
Alessandro Didonna ◽  
Anja Colja Venturini ◽  
Katrina Hartman ◽  
Tanja Vranac ◽  
Vladka Curin Serbec ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Prion Protein ◽  
Biochemical Characterization ◽  
Prion Diseases ◽  
Physiological Role ◽  
Prion Infection ◽  
Promising Tool ◽  
C Terminus ◽  
N Terminus

Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. They are characterized by the accumulation in the central nervous system of a pathological form of the host-encoded prion protein (PrPC). The prion protein is a membrane glycoprotein that consists of two domains: a globular, structured C-terminus and an unstructured N-terminus. The N-terminal part of the protein is involved in different functions in both health and disease. In the present work we discuss the production and biochemical characterization of a panel of four monoclonal antibodies (mAbs) against the distal N-terminus of PrPC using a well-established methodology based on the immunization of Prnp0/0 mice. Additionally, we show their ability to block prion (PrPSc) replication at nanomolar concentrations in a cell culture model of prion infection. These mAbs represent a promising tool for prion diagnostics and for studying the physiological role of the N-terminal domain of PrPC.

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