Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions

Bate, Clive; Williams, Alun

doi:10.1099/vir.0.80366-0

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…Extracted GPIs were applied to Silica Gel 60 high performance TLC plates (Whatman) and developed using a mixture of chloroform/methanol/water (4:4:1, v/v). GPI anchors were detected by immunoblotting as described previously (22). Plates were soaked in 0.1% poly(isobutyl methacrylate) in hexane, dried, and blocked with PBS containing 5% milk powder.…”

Section: Methodsmentioning

confidence: 99%

“…Some GPI anchors are more than a simple mechanism of attaching proteins to the cell membranes and have cell signaling functions. For example, GPIs from the protozoan Plasmodium falciparum stimulate macrophages (20), whereas other GPIs stimulate lipogenesis in adipocytes (21), and GPIs isolated from PrP C stimulate phospholipase A 2 (PLA 2 ) (22). Because PLA 2 affected the formation of prions (23), we used synthetic GPI analogues to examine the relationship between GPI anchors, lipid rafts, cell activation, and prion formation.…”

Section: Prpmentioning

confidence: 99%

“…Because the production of synthetic GPI anchors is not a trivial task, GPI anchors were isolated from three different proteins (PrP C , CD55, and Thy-1) as described previously (22). ScGT1 cells were treated daily with these GPI anchors, and the amount of PrP Sc in cell extracts was determined after 7 days.…”

Section: Paf Reversed the Effect Of Glucosamine-pi On Prpmentioning

confidence: 99%

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Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation

Bate

Tayebi

Williams³

2010

Journal of Biological Chemistry

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A hallmark of prion diseases is the conversion of the hostencoded prion protein (PrP C where C is cellular) into an alternatively folded, disease-related isoform (PrP Sc , where Sc is scrapie), the accumulation of which is associated with synapse degeneration and ultimately neuronal death. The formation of PrP Sc is dependent upon the presence of PrP C in specific, cholesterol-sensitive membrane microdomains, commonly called lipid rafts. PrP C is targeted to these lipid rafts because it is attached to membranes via a glycosylphosphatidylinositol anchor. Here, we show that treatment of prion-infected neuronal cell lines (ScN2a, ScGT1, or SMB cells) with synthetic glycosylphosphatidylinositol analogues,

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Section: Methodsmentioning

confidence: 99%

Section: Prpmentioning

confidence: 99%

Section: Paf Reversed the Effect Of Glucosamine-pi On Prpmentioning

confidence: 99%

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Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation

Bate

Tayebi

Williams³

2010

Journal of Biological Chemistry

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“…Other authors, however, found an inhibition of prion infection by using FC lowering drugs (i.e. statins) in both in vitro [18,19] and in vivo [20] prion models.…”

Section: Introductionmentioning

confidence: 99%

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

et al. 2010

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Scrapie is a prion disease for which no means of ante-mortem diagnosis is available. We recently found a relationship between cell susceptibility to scrapie and altered cholesterol homeostasis. In brains and in skin fibroblasts and peripheral blood mononuclear cells from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype, the levels of cholesterol esters were consistently higher than in tissues and cultures derived from animals with a scrapie-resistant genotype. Here we show that intracellular accumulation of cholesterol esters (CE) in fibroblasts derived from scrapie-susceptible sheep was accompanied by parallel alterations in the expression level of acyl-coenzymeA: cholesterol-acyltransferase (ACAT1) and caveolin-1 (Cav-1) that are involved in the pathways leading to intracellular cholesterol esterification and trafficking. Comparative analysis of cellular prion protein (PrPc) mRNA, showed an higher expression level in cells from animals carrying a susceptible genotype, with or without Scrapie. These data suggest that CE accumulation in peripheral cells, together with the altered expression of some proteins implicated in intracellular cholesterol homeostasis, might serve to identify a distinctive lipid metabolic profile associated with increased susceptibility to develop prion disease following infection.

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“…In proteins, for example, this can have significant effects on the intrinsic properties that can influence their stability, resistance to proteolysis, and tertiary structure which can affect the rate of processes that involve conformational changes (112,134,200). The level of glycosylation can also modulate the interaction of the glycoconjugate with other molecules (14,189). Given the significant impact of carbohydrate modifications on protein structure/ function, glycosylation of bacterial proteins is of major relevance to the molecular basis of pathogenesis.…”

Section: Gingipain Glycosylationmentioning

confidence: 99%

Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis

Sheets

Robles-Price²,

McKenzie³

et al. 2008

Front Biosci

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Porphyromonas gingivalis, a major periodontal pathogen, must acquire nutrients from host derived substrates, overcome oxidative stress and subvert the immune system. These activities can be coordinated via the gingipains which represent the most significant virulence factor produced by this organism. In the context of our contribution to this field, we will review the current understanding of gingipain biogenesis, glycosylation, and regulation, as well as discuss their role in oxidative stress resistance and apoptosis. We can postulate a model, in which gingipains may be part of the mechanism for P. gingivalis virulence. KeywordsPorphyromonas gingivalis; gingipains; apoptosis; caspase-independent apoptosis; oxidative stress; VimA; anoikis; N-cadherin; VE-cadherin; integrin β1; VimA; VimE; VimF; DNA repair; glycosylation; virulence; host cell survival; HRgpA; RgpB; Kgp; Review INTRODUCTIONP. gingivalis, a black-pigmented, Gram-negative anaerobe, is an important etiological agent of periodontal disease and is also linked to cardiovascular disease and other systemic diseases [reviewed in (43,103)]. The inflammatory nature of periodontal disease implies that innate host defense mechanisms play a vital role in limiting bacterial growth. During active infection including tissue invasion, toxic reactive oxygen metabolites (e.g. superoxides, hydrogen peroxide and hydroxyl radicals) are mostly generated by polymorphonuclear leukocytes and macrophages (27,29). In order to survive in the inflammatory environment of the periodontal pocket, the bacterium must not only obtain nutrients for growth, but also overcome oxidative stress and subvert the immune defense system. Coordinated regulation of these activities would be beneficial to the bacterium. While there is documented evidence of the response of P. gingivalis to environmental stimulus (56,117,126), one possible mechanism for coordination may occur via the gingipains produced by this bacterium. The presence of P. gingivalis in the periodontal pocket and the high levels of gingipain activity detected in gingival crevicular fluid could implicate a role for gingipains in the destruction of the highly vascular periodontal tissue. Protease-associated degradation of cell-cell adhesion proteins on epithelial and endothelial cells resulting in cell death will compromise tissue integrity and facilitate spreading of the bacterium. Furthermore, degradation of the immune response components will facilitate the survival of the organism. Together, these activities may also satisfy the nutritional requirements of the organism. Gingipain-dependent heme accumulation on the bacterium cell surface may also act as an "oxidative sink", thus, leading to protection against oxidative stress (191,193). We will discuss the role of the gingipains in the survival/pathogenicity of P. gingivalis and the unique vim (virulence modulating) locus that is involved in regulation of the gingipains. We will highlight some of our observations that are consistent with the hypothesis that the gingipain...

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Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions

Cited by 17 publications

References 32 publications

Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation

Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis

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