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ABSTRACT: The cellular prion protein (PrP(C)) is a glycoprotein anchored by glycosylphosphatidylinositol to the cell surface and is abundantly expressed in the central nervous system. A previous study has shown that PrP(C) contributes to the establishment of infections with intracellular bacteria in macrophages. In the present work, we investigated the role of PrP(C) in the response of BV2 microglia to Mycobacterium bovis infection. For this purpose, we examined the mRNA expression of prion protein gene (PRNP) upon M. bovis infection and analyzed the effect of siRNA-mediated disruption of PRNP on different parameters of microglial activation and apoptosis in M. bovis-infected microglia. We found that M. bovis infection induced a gradual increase in PRNP mRNA level and that siRNA-mediated silencing of PRNP in M. bovis-infected microglia reduced M. bovis-induced upregulation of pro-inflammatory factors, increased the rate of apoptosis in infected microglia, promoted the intrinsic apoptotic pathway, and downregulated the extrinsic apoptotic pathway. We conclude that PrP(C) participates in the regulation of the response of microglia to M. bovis infection through the upregulation of pro-inflammatory cytokines and the modulation of apoptosis by interference with the intrinsic apoptotic pathway.
Journal of Molecular Neuroscience 01/2013; · 2.50 Impact Factor
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ABSTRACT: The cellular prion protein (PrP(C) ) is a glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface and is abundantly expressed in the central nervous system. Numerous studies have suggested a protective function for PrP(C) , including protection from ischemic and excitotoxic lesions and several apoptotic insults, and recent reports have shown that PrP(C) has a context-dependent neuro-protective function. In the present study, we investigated the effect of PPNP downregulation on various forms of microglial activation. We first examined the mRNA expression of PRNP upon exposure to IFN-γ, IL-4, or IL-10 in BV2 microglia. We then analyzed the effect of si-RNA-mediated disruption of PRNP on different parameters of microglial activation in IFN-γ-, IL-4-, or IL-10-stimulated microglia. The results showed that PRNP mRNA expression was invariably downregulated in microglia upon exposure to IFN-γ, IL-4, or IL-10. PRNP silencing prior to cytokines treatment reduced the responsiveness of microglia to INF-γ treatment, significantly altered IL-4-induced microglial activation phenotype, and had no effect on IL-10-induced microglial activation. Together, these results support a role of PrP(C) in the modulation of the shift of microglia from a quiescent state to an activated phenotype and in the regulation of the microglial response during classical and alternative activation. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12053.
Journal of Neurochemistry 10/2012; · 4.06 Impact Factor
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ABSTRACT: Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The identification of cell surface molecules that mediate the prion protein (PrP) synthetic peptide interaction with microglia is of great significance as it represents potential target molecules to modulate the events leading to the pathophysiology of prion diseases. Here, we carried out in vitro experiments to investigate the involvement of α5β1 integrin in neurotoxic prion peptide PrP(106-126)-induced activation of BV2 microglia. The results showed that the exposure to PrP(106-126) upregulated the mRNA expression of proinflammatory factors (IL-1 β, IL-6, and iNOS) and NALP3 inflammasome components (NALP3 and ASC), increased the release of iNOS and its product nitric oxide, and stimulated NF-κB activation. Blockade of α5β1 integrin with monoclonal antibody BMC5 prior to PrP(106-126) treatment abrogated the upregulation of the mRNA expression of IL-1 β, IL-6, iNOS, and ASC, but had no effect on the mRNA expression of NALP3, blocked the release of iNOS and nitric oxide, and inhibited NF-κB activation. These results suggest that α5β1 integrin is involved in the PrP(106-126)-induced microglial activation through the participation in the activation of NF-κB and NALP3/ASC inflammasome. Our study unveils a previously unidentified role of α5β1 integrin as an intermediate signaling molecule in neurotoxic prion peptides-microglia interactions and identifies a potential molecular target for the modulation of prion-induced microglial activation.
Journal of Molecular Neuroscience 05/2012; 48(1):248-52. · 2.50 Impact Factor
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ABSTRACT: Mycobacterium bovis parasitizes host macrophages and has developed strategies to survive within macrophages. Research on mycobacteria-specific PE_PGRS genes indicates that they code for cell surface proteins that may influence virulence. To further elucidate the molecular pathogenesis of tuberculosis and host response to M. bovis, we explored the mechanisms by which PE_PGRS62 protein increase persistence of mycobacterium within host macrophages. We found that the M. smegmatis strain expressing M. bovis PE_PGRS 62 protein reduced phagolysosome maturation in human macrophages, and significantly decreased the mRNA expression of IL-1β in a dose- and time-dependent. We identified that IFN-γ priming of macrophages immediately prior to infection with PE_PGRS62 expressing M. smegmantis, enhanced the maturation of phagolysosomes and induced IL-1β production both that the protein and mRNA levels and further activated the NF-κB pathway. Overall, we demonstrated that PE_PGRS62 protein altered the immune environment of the host cells, which suggested that the pathogenic PE_PGRS62 protein altering the immune mechanism might be involved in the pathogenesis of mycobacterial disease and hence influenced host cell responses to M. bovis infection.
Veterinary Microbiology 05/2012; 160(1-2):117-25. · 3.33 Impact Factor
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ABSTRACT: Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. In prion-infected brains, activated microglia are often present in the vicinity of PrPSc aggregates, and microglial activation is thought to play a key role in the pathogenesis of prion diseases. Although interleukin (IL)-1β release by prion-induced microglia has been widely reported, the mechanism by which primed microglia become activated and secrete IL-1β in prion diseases has not yet been elucidated. In this study, we investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP)3 inflammasome in IL-1β release from lipopolysaccharide (LPS)-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126).
The inflammasome components NALP3 and apoptosis-associated speck-like protein (ASC) were knocked down by gene silencing. IL-1β production was assessed using ELISA. The mRNA expression of NALP3, ASC, and pro-inflammatory factors was measured by quantitative PCR. Western blot analysis was used to detect the protein level of NALP3, ASC, caspase-1 and nuclear factor-κB.
We found that that PrP106-126-induced IL-1β release depends on NALP3 inflammasome activation, that inflammasome activation is required for the synthesis of pro-inflammatory and chemotactic factors by PrP106-126-activated microglia, that inhibition of NF-κB activation abrogated PrP106-126-induced NALP3 upregulation, and that potassium efflux and production of reactive oxygen species were implicated in PrP106-126-induced NALP3 inflammasome activation in microglia.
We conclude that the NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. To our knowledge, this is the first time that strong evidence for the involvement of NALP3 inflammasome in prion-associated inflammation has been found.
Journal of Neuroinflammation 04/2012; 9:73. · 3.83 Impact Factor
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ABSTRACT: Astrogliosis is a hallmark of prion disease, but the metabolic alterations of astrocytes remain poorly documented. A synthetic
peptide corresponding to amino acid 106–126 of the human prion protein (PrP) has been shown to be toxic to neurons. In this
study, the effects of PrP 106–126 on astrocytes were investigated in vitro. The proliferation of astrocytes was significantly (P < 0.05) increased when grown in media conditioned with PrP 106–126 (80 μmol/L) from microglia. The expression of laminin
(LN) and fibronectin (FN) was examined at both mRNA and protein levels. The results showed that exposure of astrocytes to
PrP 106–126 enhanced the expression of LN and FN. The increase of FN in astrocyte cultures required cytokines previously released
by activated microglia. This study reveals the expression of LN and FN affected by PrP106–126.
Chinese Science Bulletin 04/2012; 53(14):2160-2164. · 1.32 Impact Factor
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ABSTRACT: The key point, which is related to the susceptibility of prion diseases in animals, has been proved to be the prion protein gene (PRNP). However, animals, especially sheep and goats, with the same PRNP genotype are not equally susceptible to the diseases. The finding of SPRN (shadow of prion protein homology) provides a new aspect to understand the diseases as protein of SPRN (Shadoo) has similar neuroprotective function and conserved hydrophobic core with prion protein (PrP). Researchers have made some efforts to demonstrate the relationship between SPRN and PRNP. Stewart's work has shown that SPRN contained an alanine-rich sequence, which is homologous to a hydrophobic core with amyloidgenic characteristics in PrP. Here our work shows that the sheep of Inner Mongolia in China have several haplotypes with the similar results of Stewart and Daude's. However we find a new haplotype in a Sunite sheep, which is not reported by others.
Virus Genes 02/2012; 44(3):548-50. · 1.85 Impact Factor
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ABSTRACT: Up to now, little is known about the prion protein gene (PRNP) of domestic bactrian camels, and no polymorphisms of the bactrian camel PRNP have been analyzed or reported. In this study, we cloned and analyzed the PRNP sequences of 89 domestic bactrian camels. The results showed that the amino acid sequence of bactrian camel PrP starts with the consensus sequence MVKSH, with almost identical amino acid sequence to the PrP of dromedary camels. A four octapeptide PHGGGWGQ repeat region follows a nonapeptide (PQGGGGWGQ) in the N-terminal of deduced amino acid sequence from residues 54 to 95. Polymorphisms of PRNP in both species of camels were observed in codons 16(A→V), 17(M→T), 120(N→S), 176(R→K), 215(I→V), 234(S→Y), 237(Y→S), and 239(Q→G) by comparing with other ruminants. The PrP gene nucleotide sequence alignments of bactrian camels (HQ204566.1 and HQ204567.1) showed high identity with dromedary camel (99.2%, 99.1%), sheep (91.9%, 91.8%) and cattle (91.8%, 91.6%). This study provides valuable data for future research on susceptibility or resistance of camels to prion diseases.
Gene 01/2012; 491(2):256-9. · 2.34 Impact Factor
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PLoS ONE 01/2012; 7(2). · 4.09 Impact Factor
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ABSTRACT: Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106-126 (PrP(106-126)). We first examined the time course of CD36 mRNA expression upon exposure to PrP(106-126) in BV2 microglia. We then analyzed different parameters of microglial activation in PrP(106-126)-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP(106-126). The results showed that PrP(106-126) treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP(106-126)-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP(106-126)-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP(106-126)-treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP(106-126). Together, these results suggest that CD36 is involved in PrP(106-126)-induced microglial activation and that the participation of CD36 in the interaction between PrP(106-126) and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling.
PLoS ONE 01/2012; 7(1):e30756. · 4.09 Impact Factor
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ABSTRACT: The inflammatory response in prion diseases is dominated by microglia activation. The molecular mechanisms that lie behind this inflammatory process are not very well understood. In the present study, we examined the activat2ion of nuclear factor-kappa B (NF-κB) upon exposure to PrP106-126 and its role in PrP106-126-induced upregulation of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6) in Ana-1 macrophages. The results showed that iNOS and proinflammatory cytokine release was significantly elevated in Ana-1 macrophages upon exposure to PrP106-126; that PrP106-126 treatment led to a significant NF-κB activation; that proinflammatory cytokines gene expression was elevated in macrophages upon exposure to PrP106-126; and that NF-κB inhibition significantly abrogated PrP106-126-induced upregulation of iNOS and inflammatory cytokine mRNA expression. These results suggest that treatment with neurotoxic prion peptides leads to the activation of transcription factor NF-κB, which in turn stimulates gene expression of iNOS and proinflammatory cytokines in Ana-1 macrophages.
DNA and cell biology 12/2011; 31(5):833-8. · 2.28 Impact Factor
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ABSTRACT: The resistance or susceptibility of sheep to scrapie is associated with polymorphisms of the prion protein gene (PRNP), particularly, single nucleotide polymorphisms (SNPs) in amino acid positions 136, 154 and 171. The prion protein (PrP) gene sequence and the deduced amino acid alignment of prion protein in Tan sheep, a local Chinese sheep breed traditionally raised in Ningxia, northwestern China, were determined and variability of the PrP amino acids sequence was analyzed in this study. The PrP nucleic acids and amino acids sequences of 112 Tan sheep were highly homogenous, although polymorphism of the PrP gene was detected at several sites, particularly codons 106, 154, and 171. The analysis of both sequences revealed that the most predominant allele at codons 136, 154 and 171 in Tan sheep was ARQ, which was known to be associated with high susceptibility to scrapie in sheep. The result suggests that Tan sheep is potentially susceptible to scrapie. Our findings provide valuable information for future breeding projects to scrapie resistance in Tan sheep.
Gene 06/2011; 485(2):102-5. · 2.34 Impact Factor
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ABSTRACT: The inflammatory responses in Alzheimer's disease and prion diseases are dominated by microglia activation. Scavenger receptors have been recently related to the innate immune activation of microglia initiated by endogenous ligands. In this study, we investigated mRNA expression patterns of B class scavenger receptors CD36 and scavenger receptor B1 (SR-B1) in BV2 microglia upon exposure to amyloid fibril Aβ(1-42) and PrP(106-126), respectively. CD36 and SR-B1 showed similar mRNA expression patterns following each treatment. PrP(106-126) induced a rapid increase of CD36 and SR-B1 mRNA levels in the treated microglia, whereas Aβ(1-42) induced a delayed but persistent increase in the mRNA expression of CD36 and SR-B1. These results suggest a possible involvement of CD36 and SR-B1 in microglial interaction with amyloidogenic fragments of beta-amyloid and prion proteins.
DNA and cell biology 06/2011; 30(11):893-7. · 2.28 Impact Factor
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ABSTRACT: Bovine tuberculosis (BTB) is a chronic infectious disease caused by the pathogen Mycobacterium bovis and poses a long-standing threat to livestock worldwide. To further elucidate the poorly defined BTB immune response in cattle, we utilized monocyte-derived macrophages (MDMs) to assess the gene expression related to M. bovis Beijing strain stimulation. Here, we demonstrate the existence of distinctive gene expression patterns between macrophages of healthy cattle and those exposed to BTB. In comparing MDMs cells from healthy cattle (n=5) and cattle with tuberculosis (n=5) 3 h after M. bovis stimulation, the differential expressions of seven genes (IL1β, IL1R1, IL1A, TNF-α, IL10, TLR2 and TLR4) implicated in M. bovis response were examined. The expressions of these seven genes were increased in both the tuberculosis-infected and the healthy cattle to M. bovis stimulation, and two of them (TLR2 and IL10) were significantly different in the tuberculosis and the healthy control groups (P≤0.05). The increase in the expression of the TLR2 gene is more significant in healthy cattle response to stimulation, and the change of IL10 gene expression is more significant in tuberculosis cattle. Additionally, we investigated the cytopathic effect caused by M. bovis stimulation and the relationship between M. bovis and MDMs cells to obtain a general profile of pathogen-host interaction.
FEMS Microbiology Letters 05/2011; 321(1):30-6. · 2.04 Impact Factor
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ABSTRACT: Macrophage apoptosis represents an important innate defense mechanism against intracellular mycobacterial infection. Previous publications have shown that interferon-γ (IFN-γ) is involved in apoptosis of immune cells infected with mycobacteria. In this study, the impact of IFN-γ treatment on phorbol-12-myristate-13-acetate-differentiated THP-1 cells infected with Mycobacterium bovis was investigated. The results showed that IFN-γ increased apoptosis of THP-1 cells infected with M. bovis at a low multiplicity of infection (MOI) in a time-dependent manner. The percentage of cells undergoing apoptosis in IFN-γ-treated THP-1 cells increased from 4.3% at 12 h to 36.5% at 72 h upon infection with an MOI of 10. Activation of caspases-3 and -8 increased 8.3- and 6.7-fold, respectively. Neutralizing endogenous tumor necrosis factor-α (TNF-α) significantly inhibited IFN-γ-induced apoptosis of M. bovis-infected THP-1 cells. No significant change in IFN-γ-induced apoptosis was observed in M. bovis-infected cells after the addition of c-Jun N-terminal kinase and NF-κB pathways' inhibitors. Translocation of apoptosis-inducing factor (AIF) to the nucleus of M. bovis-infected THP-1 cells was observed in 23.4% of IFN-γ-treated cells, compared with 11.0% in untreated cells. Taken together, these results suggest that IFN-γ promotes apoptosis of M. bovis-infected THP-1 cells during early infection through the TNF-α-mediated death receptor and the AIF apoptotic pathway.
FEMS Immunology & Medical Microbiology 12/2010; 60(3):191-8. · 2.44 Impact Factor
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ABSTRACT: PrPC (cellular prion protein) is a GPI (glycophosphatidylinositol)-anchored protein present on the surface of a number of peripheral blood cells. PrPC must be present for the generation and propagation of pathogenic conformer [PrPSc (scrapie prion protein)], which is a conformational conversion form of PrPC and has a central role in transmissible spongiform encephalopathies. It is important to determine the transportation mechanism of normal PrPC between cells. Exosomes are membrane vesicles released into the extracellular space upon fusion of multivesicular endosomes with the plasma membrane. We have identified that THP-1 monocytes can secrete exosomes to culture medium, and the secreted exosomes can bear PrPC. We also found that Hsp70 interacts with PrPC not only in intracellular environment, but in the secreted exosomes. However, the specific markers of exosomes, Tsg101 and flotillin-1, were found with no interaction with PrPC. Our results demonstrated that PrPC can be released from THP-1 monocytes via secreted exosomes, and in this process, Hsp70 binds to PrPC, which suggests that Hsp70 may play a potential functional role in the release of PrPC.
Cell Biology International 10/2010; 35(6):553-8. · 1.48 Impact Factor
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ABSTRACT: Prion diseases are infectious and fatal neurodegenerative disorders. The cellular prion protein (PrP(C)) converting into misfolded isoform of prion protein (PrP(Sc)) is responsible for prion disease infection. Immune system plays an important role in facilitating the spread of prion infections from the periphery to the central nervous system. Macrophages were considered associated with the transportation and replication of PrP(Sc). So, understanding the PrP(C) trafficking in macrophages is important to explore the transport mechanism for PrP(Sc). Here, we isolated exosomes from the culture medium of Ana-1 macrophage cell line and investigated the PrP(C) trafficked by exosomes and the interaction of PrP(C) with Hsp70 in secreted exosomes by western blotting, immunoelectron microscopy, and co-immunoprecipitation. The results showed that the isolated vesicles from the culture medium of macrophages were characterized by exosomes and bore PrP(C). And PrP(C) bound to Hsp70 both in intracellular environment and secreted exosomes. In contrast, PrP(C) had no interaction with marker proteins of exosomes, Tag101 and Flotillin-1. These results suggested that PrP(C) present in extracellular space might be externalized through secreted exosomes from macrophages, and Hsp70 may play roles in the process of PrP(C) released via secreted exosomes.
Acta Biochimica et Biophysica Sinica 05/2010; 42(5):345-50. · 1.38 Impact Factor
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ABSTRACT: Prion diseases are characterized by accumulation of protease resistant isoforms of prion protein (PrP), and infiltration and activation of mononuclear phagocytes at the brain lesions. Interactions between prion proteins and immune cells during disease progression are still not very well understood. In the present study, multiwell chamber chemotaxis assay was carried out to assess the migratory response of macrophage cell line Ana-1 to a synthetic peptide homologous to residues 106-126 of the human prion protein. Specific protein kinase inhibitors were used to elucidate the signaling events underlying PrP106-126-induced macrophages migration, and a comparison with the signaling pattern of macrophage migration induced by substance P (SP) and N-formyl-methionyl-leucyl-phenylalanine (fMLP), respectively, was carried out. The results showed that PrP106-126 had a potent chemotactic effect on murine macrophage cell line Ana-1; that multiple signaling pathways might be involved in the PrP106-126-induced macrophage migrations; and that PrP106-126-induced chemotactic activity was similar to that induced by SP. These findings provide new insights into the mechanisms underlying the interaction between PrP and macrophages.
Journal of neuroscience methods 05/2009; 181(1):1-5. · 2.30 Impact Factor
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ABSTRACT: The 37-kDa Laminin Receptor Precursor (LRP)/67-kDa Laminin Receptor (LR), also known as ribosomal protein SA (RPSA), had been identified as a putative cell surface receptor for prions. Herein, we isolated the full-length coding sequence (CDS) of the ovine 37/67-kDa LRP/LR gene and submitted it to the GenBank under accession number EF649775. The open reading frame (ORF) of the 37/67-kDa LRP/LR CDS is 885 bp in length, containing six exons encoding a protein of 295 amino acids. The nucleotide sequence presented here is well coincided with the whole ovine genome of the 37/67-kDa LRP/LR previously published. Moreover, we identified four novel single nucleotide polymorphism sites (SNPs) at position 324 in exon 4, positions at 809, 875, and 881 in exon 7, respectively. Further, based on the deduced amino acid sequence alignment of the 37/67-kDa LRP/LR from human, cattle, mice, pig, chicken, and sheep, we also identified three polymorphic amino acid sites (PAAs) at residues 241, 272, and a novel site at residue 270 in the putative indirect prion protein (PrP) interaction region (180-285) on 37/67-kDa LRP/LR. Prediction of protein secondary structure further indicated that PAAs at residues 241, 270 and 272 may cause protein conformation changes as predicted, which may affect on the binding with prion protein. In addition, multiple-tissues RT-PCR results revealed that 37/67-kDa LRP/LR mRNA is expressed in all the 11 selected ovine tissues.
Molecular Biology Reports 01/2009; 36(8):2131-7. · 2.93 Impact Factor
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ABSTRACT: Neuronal death is a pathological hallmark of prion diseases. Synthetic prion peptide PrP106-126 can convert PrP(C) into protease-resistant aggregates, which can cause neurotoxicity in vivo and in vitro. Various cell surface proteins can participate in the infection process of prions. p75(NTR) can interact with PrP106-126 and has a neurotoxic effect on neurons. However, for p75(NTR) lacking intrinsic catalytic activity domain in cytoplasm, p75(NTR) -associated signaling molecular and the signaling events in cytoplasm in p75(NTR)-mediated apoptosis responding to PrP106-126 remain still unknown. Thus p75(NTR) -associated NF-kappaB signaling pathway was investigated in this study. Herein PrP106-126-induced apoptosis in mouse neuroblastoma cell line N2a, PrP106-126 significantly up-regulated p75(NTR) expression on mRNA and protein levels. For the first time we found that PrP106-126 induced activation of NF-kappaB by Western blot assay, and blocking the interaction of p75(NTR) with PrP106-126 by p75(NTR) polyclonal antibody sc-6189 or pretreatment with inhibitor NF-kappaB SN50 reduced the activation of NF-kappaB and attenuated the apoptotic effect by PrP106-126. This study offers a possible interpretation that NF-kappaB signaling pathway was activated by the interaction of PrP106-126 with p75(NTR), and NF-kappaB activity showed the pro-apoptotic effect in PrP106-126-induced apoptosis in N2a cells. Involvement of NF-kappaB signaling pathway in p75(NTR)-mediated apoptosis may partially account for the PrP106-126-induced neurotoxicity in N2a cells.
Neuroscience Research 06/2008; 62(1):9-14. · 2.25 Impact Factor
