Cross-Linking Cellular Prion Protein Triggers Neuronal Apoptosis in Vivo

Science ◽  
2004 ◽  
Vol 303 (5663) ◽  
pp. 1514-1516 ◽  
Author(s):  
L. Solforosi
Keyword(s):  
Prion Protein ◽  
Neuronal Apoptosis ◽  
Cellular Prion Protein ◽  
Cross Linking

Mitochondrial localization of cellular prion protein (PrPC) invokes neuronal apoptosis in aged transgenic mice overexpressing PrPC

2005 ◽  
Vol 374 (2) ◽  
pp. 98-103 ◽  
Author(s):  
Naomi S. Hachiya ◽  
Makiko Yamada ◽  
Kota Watanabe ◽  
Akiko Jozuka ◽  
Takuya Ohkubo ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Neuronal Apoptosis ◽  
Cellular Prion Protein ◽  
Mitochondrial Localization

The cellular prion protein binds copper in vivo

Nature ◽  
10.1038/37783 ◽  
1997 ◽  
Vol 390 (6661) ◽  
pp. 684-687 ◽  
Author(s):  
David R. Brown ◽  
Kefeng Qin ◽  
Jochen W. Herms ◽  
Axel Madlung ◽  
Jean Manson ◽  
...  
Keyword(s):  
Prion Protein ◽  
Cellular Prion Protein

scholarly journals Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7–PSD-95 binding

2011 ◽  
Vol 22 (17) ◽  
pp. 3041-3054 ◽  
Author(s):  
Patricia Carulla ◽  
Ana Bribián ◽  
Alejandra Rangel ◽  
Rosalina Gavín ◽  
Isidro Ferrer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Knockout Mice ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Glycosyl Phosphatidylinositol

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol–anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-d-aspartic acid (NMDA)–mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6–PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

scholarly journals Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1421-1434 ◽  
Author(s):  
CLAUDIA P. FIGUEIREDO ◽  
NATALIA C. FERREIRA ◽  
GISELLE F. PASSOS ◽  
ROBSON DA COSTA ◽  
FERNANDA S. NEVES ◽  
...  
Keyword(s):  
Prion Protein ◽  
Aromatic Compounds ◽  
Prion Diseases ◽  
Intraperitoneal Administration ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Toxicological Evaluation ◽  
Spongiform Encephalopathies

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.

scholarly journals mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Neng-Wei Hu ◽  
Andrew J. Nicoll ◽  
Dainan Zhang ◽  
Alexandra J. Mably ◽  
Tiernan O’Malley ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Long Term Depression ◽  
Mglu5 Receptors

scholarly journals Expression and characterisation of fully posttranslationally modified cellular prion protein in Pichia pastoris

2013 ◽  
Vol 394 (11) ◽  
pp. 1475-1483
Author(s):  
Jendrik Marbach ◽  
Peter Zentis ◽  
Philipp Ellinger ◽  
Henrik Müller ◽  
Eva Birkmann
Keyword(s):  
Plasma Membrane ◽  
Pichia Pastoris ◽  
Prion Protein ◽  
Prion Diseases ◽  
Phosphatidyl Inositol ◽  
Cellular Prion Protein ◽  
Glycosylation Pattern ◽  
Signal Sequences

Abstract Prion diseases are fatal neurodegenerative diseases which occur as sporadic, genetic, and transmissible disorders. A molecular hallmark of prion diseases is the conformational conversion of the host-encoded cellular form of the prion protein (PrPC) into its misfolded pathogenic isoform (PrPSc). PrPSc is the main component of the pathological and infectious prion agent. The study of the conversion mechanism from PrPC to PrPSc is a major field in prion research. PrPC is glycosylated and attached to the plasma membrane via its glycosyl phosphatidyl inositol (GPI)-anchor. In this study we established and characterised the expression of fully posttranslationally modified mammalian Syrian golden hamster PrPC in the yeast Pichia pastoris using native PrPC-specific N- and C-terminal signal sequences. In vivo as well as in vitro-studies demonstrated that the signal sequences controlled posttranslational processing and trafficking of native PrPC, resulting in PrPC localised in the plasma membrane of P. pastoris. In addition, the glycosylation pattern of native PrPC could be confirmed.

scholarly journals Prion protein attenuates excitotoxicity by inhibiting NMDA receptors

2008 ◽  
Vol 181 (3) ◽  
pp. 551-565 ◽  
Author(s):  
Houman Khosravani ◽  
Yunfeng Zhang ◽  
Shigeki Tsutsui ◽  
Shahid Hameed ◽  
Christophe Altier ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Prion Protein ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Physiological Role ◽  
Cellular Prion Protein ◽  
Glutamate Excitotoxicity ◽  
Null Mouse

It is well established that misfolded forms of cellular prion protein (PrP [PrPC]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrPC remains incompletely understood. To determine the physiological role of PrPC, we examine the neurophysiological properties of hippocampal neurons isolated from PrP-null mice. We show that PrP-null mouse neurons exhibit enhanced and drastically prolonged N-methyl-d-aspartate (NMDA)–evoked currents as a result of a functional upregulation of NMDA receptors (NMDARs) containing NR2D subunits. These effects are phenocopied by RNA interference and are rescued upon the overexpression of exogenous PrPC. The enhanced NMDAR activity results in an increase in neuronal excitability as well as enhanced glutamate excitotoxicity both in vitro and in vivo. Thus, native PrPC mediates an important neuroprotective role by virtue of its ability to inhibit NR2D subunits.

scholarly journals OPA1 overexpression ameliorates mitochondrial cristae remodeling, mitochondrial dysfunction, and neuronal apoptosis in prion diseases

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Wei Wu ◽  
Deming Zhao ◽  
Syed Zahid Ali Shah ◽  
Xixi Zhang ◽  
Mengyu Lai ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neuronal Apoptosis ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Primary Neurons ◽  
Mitochondrial Network ◽  
Mitochondrial Dynamic ◽  
Structure Damage

Abstract Prion diseases caused by the cellular prion protein (PrPC) conversion into a misfolded isoform (PrPSc) are associated with multiple mitochondrial damages. We previously reported mitochondrial dynamic abnormalities and cell death in prion diseases via modulation of a variety of factors. Optic atrophy 1 (OPA1) is one of the factors that control mitochondrial fusion, mitochondrial DNA (mtDNA) maintenance, bioenergetics, and cristae integrity. In this study, we observed downregulation of OPA1 in prion disease models in vitro and in vivo, mitochondria structure damage and dysfunction, loss of mtDNA, and neuronal apoptosis. Similar mitochondria findings were seen in OPA1-silenced un-infected primary neurons. Overexpression of OPA1 not only alleviated prion-induced mitochondrial network fragmentation and mtDNA loss, decrease in intracellular ATP, increase in ADP/ATP ratio, and decrease in mitochondrial membrane potential but also protected neurons from apoptosis by suppressing the release of cytochrome c from mitochondria to cytosol and activation of the apoptotic factor, caspase 3. Our results demonstrated that overexpression of OPA1 alleviates prion-associated mitochondrial network fragmentation and cristae remodeling, mitochondrial dysfunction, mtDNA depletion, and neuronal apoptosis, suggesting that OPA1 may be a novel and effective therapeutic target for prion diseases.

scholarly journals Mutated but Not Deleted Ovine PrPCN-Terminal Polybasic Region Strongly Interferes with Prion Propagation in Transgenic Mice

2015 ◽  
Vol 90 (3) ◽  
pp. 1638-1646 ◽  
Author(s):  
Manal Khalifé ◽  
Fabienne Reine ◽  
Sophie Paquet-Fifield ◽  
Johan Castille ◽  
Laetitia Herzog ◽  
...  
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Major Effect ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Structural Variations ◽  
Prion Propagation ◽  
Polybasic Region

ABSTRACTMammalian prions are proteinaceous infectious agents composed of misfolded assemblies of the host-encoded, cellular prion protein (PrP). Physiologically, the N-terminal polybasic region of residues 23 to 31 of PrP has been shown to be involved in its endocytic trafficking and interactions with glycosaminoglycans or putative ectodomains of membrane-associated proteins. Several recent reports also describe this PrP region as important for the toxicity of mutant prion proteins and the efficiency of prion propagation, bothin vitroandin vivo. The question remains as to whether the latter observations made with mouse PrP and mouse prions would be relevant to other PrP species/prion strain combinations given the dramatic impact on prion susceptibility of minimal amino acid substitutions and structural variations in PrP. Here, we report that transgenic mouse lines expressing ovine PrP with a deletion of residues 23 to 26 (KKRP) or mutated in this N-terminal region (KQHPH instead of KKRPK) exhibited a variable, strain-dependent susceptibility to prion infection with regard to the proportion of affected mice and disease tempo relative to findings in their wild-type counterparts. Deletion has no major effect on 127S scrapie prion pathogenesis, whereas mutation increased by almost 3-fold the survival time of the mice. Deletion marginally affected the incubation time of scrapie LA19K and ovine bovine spongiform encephalopathy (BSE) prions, whereas mutation caused apparent resistance to disease.IMPORTANCERecent reports suggested that the N-terminal polybasic region of the prion protein could be a therapeutic target to prevent prion propagation or toxic signaling associated with more common neurodegenerative diseases such as Alzheimer's disease. Mutating or deleting this region in ovine PrP completes the data previously obtained with the mouse protein by identifying the key amino acid residues involved.

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