Phospholipase A2 Inhibitors or Platelet-activating Factor Antagonists Prevent Prion Replication

Bate, Clive; Reid, S. W. J.; Williams, Alun

doi:10.1074/jbc.m404086200

Cited by 44 publications

(47 citation statements)

References 44 publications

(41 reference statements)

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“…However, Thy-1, a GPI-anchored protein also localized to lipid rafts, occupies slightly different domains on the plasma membrane compared to those occupied by PrP (5). In addition, the GPI anchor of PrP, but not the GPI anchor of Thy-1, can activate phospholipase 2, a protein involved in apoptosis (2). Therefore, the difference in amino acid sequence around the site may cause the GPI anchor of RbPrP to be modified so that it does not support prion propagation.…”

Section: Discussionmentioning

confidence: 99%

“…GPI anchors contain a conserved core of ethanolamine phosphate in an amide linkage to the C terminus of the protein, three mannose residues, glucosamine, and phosphatidylinositol (2,27). When the protein migrates to the plasma membrane, the GPI anchors are modified so that many variations on this core structure arise.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were grown in a Transwell system (pore size, 0.4 m; Nunc), and the electrical resistance (TER) was measured daily with a Millicell-ERS instrument (Millipore) until a stable TER (100 ⍀ ⅐ cm 2 …”

Section: Methodsmentioning

confidence: 99%

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Residues Surrounding the Glycosylphosphatidylinositol Anchor Attachment Site of PrP Modulate Prion Infection: Insight from the Resistance of Rabbits to Prion Disease

Nisbet

Harrison

Lawson

et al. 2010

J Virol

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Prion diseases are a group of transmissible, invariably fatal neurodegenerative diseases that affect both humans and animals. According to the protein-only hypothesis, the infectious agent is a prion (proteinaceous infectious particle) that is composed primarily of PrP Sc , the disease-associated isoform of the cellular prion protein, PrP. PrP Sc arises from the conformational change of the normal, glycosylphosphatidylinositol (GPI)-anchored protein, PrP C . The mechanism by which this process occurs, however, remains enigmatic. Rabbits are one of a small number of mammalian species reported to be resistant to prion infection. Sequence analysis of rabbit PrP revealed that its C-terminal amino acids differ from those of PrP from other mammals and may affect the anchoring of rabbit PrP through its GPI anchor. Using a cell culture model, this study investigated the effect of the rabbit PrP-specific C-terminal amino acids on the addition of the GPI anchor to PrP C , PrP C localization, and PrP Sc formation. The incorporation of rabbit-specific C-terminal PrP residues into mouse PrP did not affect the addition of a GPI anchor or the localization of PrP. However, these residues did inhibit PrP Sc formation, suggesting that these rabbit-specific residues interfere with a C-terminal PrP Sc interaction site.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Residues Surrounding the Glycosylphosphatidylinositol Anchor Attachment Site of PrP Modulate Prion Infection: Insight from the Resistance of Rabbits to Prion Disease

Nisbet

Harrison

Lawson

et al. 2010

J Virol

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“…Samples were centrifuged at 600 ϫ g for 10 min and at 100,000 ϫ g for 60 min. Cytosolic supernatants were concentrated using an Amicon centrifuge concentrator with a molecular mass cut-off of 10,000 kDa (Millipore 4 plates/condition were removed from the incubator and were placed on ice. One ml of methanol acidified with 2% acetic acid was added to each plate, and the extracellular fraction was collected.…”

Section: Methodsmentioning

confidence: 99%

“…Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1)(2)(3)(4)(5)(6)(7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8,9).…”

mentioning

confidence: 99%

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Bonin¹,

Ryan²,

Migahed³

et al. 2004

Journal of Biological Chemistry

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Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by ϳ15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I ␣ 1 regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I ␣ 2 expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I ␣ 2 homodimer activity by reducing PAF-AH I ␣ 1 expression. These findings identify PAF-AH I ␣ 2 as a potent antiapoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1-7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8, 9). Although the majority of PAF effects are understood to be transduced by its G-protein-coupled receptor (PAFR) (10), PAFR signaling has been shown to be both pro-and anti-apoptotic. Ectopic PAFR expression exacerbates cell death induced by etoposide and mitomycin C but protects cells from tumor necrosis factor ␣, TRAIL, and extracellular PAF (6,7,11,12). These opposing effects likely depend upon the relative ratio of NF-B-dependent pro-and anti-apoptotic gene products elicited in different cell types in response to the combination of an external apoptotic inducer and PAF (6).Accumulating evidence points to additional PAF signaling pathways transduced independently of PAFR (11, 13-17). PAFR-negative cells undergo apoptosis when extracellular PAF concentrations reach 100 nM and necrosis when PAF levels e...

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Prion Disease Therapy: Trials and Tribulations

Sim

Caughey

2010

Protein Misfolding Diseases

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Phospholipase A2 Inhibitors or Platelet-activating Factor Antagonists Prevent Prion Replication

Abstract: A key feature of prion diseases is the conversion of the cellular prion protein (PrP C ) into disease-related isoforms (PrP Sc ), the deposition of which is thought to lead to neurodegeneration. In this study a pharmacological approach was used to determine the metabolic pathways

Cited by 44 publications

References 44 publications

Residues Surrounding the Glycosylphosphatidylinositol Anchor Attachment Site of PrP Modulate Prion Infection: Insight from the Resistance of Rabbits to Prion Disease

Residues Surrounding the Glycosylphosphatidylinositol Anchor Attachment Site of PrP Modulate Prion Infection: Insight from the Resistance of Rabbits to Prion Disease

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Prion Disease Therapy: Trials and Tribulations

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