The Stimulation of Inducible Nitric-oxide Synthase by the Prion Protein Fragment 106–126 in Human Microglia Is Tumor Necrosis Factor-α-dependent and Involves p38 Mitogen-activated Protein Kinase

Fabrizi, Cinzia; Silei, Valerio; Menegazzi, Marta; Salmona, Mario; Bugiani, Orso; Tagliavini, Fabrizio; Suzuki, Hisanori; Lauro, Giuliana M.

doi:10.1074/jbc.m100133200

Cited by 62 publications

(54 citation statements)

References 37 publications

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“…While conducting our analysis of the data this result was initially confusing. Many of the pathways generated from the peptide array data were results that had been observed 24 and inducible nitric oxide synthase (iNOS) activation 21 which we have observed in this study. Interestingly, neuronal cells stimulated with PrP 106-126 also show iNOS and had among the highest phosphorylation levels (at targets Y151, S909 and S739) and the highest statistical significance of any peptide studied (p values of 1.6 × 10 -3 , 1.6 × 10 -3 , and 3.1 × 10 -4 respectively).…”

Section: Resultsmentioning

confidence: 52%

“…A central challenge to understanding the molecular basis of TSEs is determining whether the The PrP 106-126 peptide fragment has been widely utilized as an experimental ligand to model prion effects and this made it an ideal stimulant of PrP C signaling. 17,[20][21][22][23][24] In addition, 6H4 is a well-characterized, commercially-available monoclonal antibody for PrP C . Prion protein specific antibody has been utilized to "activate" PrP C through direct binding for investigations of PrP C function.…”

Section: Introductionmentioning

confidence: 99%

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Induction of ligand-specific PrP^Csignaling in human neuronal cells

Arsenault

Potter

et al. 2012

Prion

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Section: Resultsmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Induction of ligand-specific PrP^Csignaling in human neuronal cells

Arsenault

Potter

et al. 2012

Prion

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“…Evidence suggests that the mechanisms of neuroprotection involve inhibition of caspase-1, caspase-3, and inducible nitric oxide (NO) synthase expression and͞or NO-mediated toxicity. These properties could be beneficial also in prion-related encephalopathies, because PrP amyloid peptides have the ability to induce caspase activation and NO synthase expression in vitro (46,47), and a large number of activated caspase-3-immunoreactive cells have been observed in the brain of prion disease patients (A. Migheli, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Tetracyclines affect prion infectivity

Forloni¹,

Iussich²,

Awan³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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178

102

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Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, protease-resistant forms of the prion protein (PrP) termed PrP Sc are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Based on previous findings that tetracyclines revert abnormal physicochemical properties and abolish neurotoxicity of PrP peptides in vitro, we tested the ability of these compounds to interact with PrP Sc from patients with the new variant of Creutzfeldt-Jakob disease (vCJD) and cattle with bovine spongiform encephalopathy (BSE). The incubation with tetracycline hydrochloride or doxycycline hyclate at concentrations ranging from 10 M to 1 mM resulted in a dose-dependent decrease in protease resistance of PrP Sc . This finding prompted us to investigate whether tetracyclines affect prion infectivity by using an animal model of disease. Syrian hamsters were injected intracerebrally with 263K scrapie-infected brain homogenate that was coincubated with 1 mM tetracycline hydrochloride, 1 mM doxycycline hyclate, or vehicle solution before inoculation. Hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. These effects were paralleled by a delay in the appearance of magnetic-resonance abnormalities in the thalamus, neuropathological changes, and PrP Sc accumulation. When tetracycline was preincubated with highly diluted scrapie-infected inoculum, one third of hamsters did not develop disease. Our data suggest that these well characterized antibiotics reduce prion infectivity through a direct interaction with PrP Sc and are potentially useful for inactivation of BSE-or vCJD-contaminated products and prevention strategies.

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“…It has been demonstrated that prion protein fragment (PrP106-126) is neurotoxic 48) and induces microglial activation of iNOS expression and TNFa production. 49) Activation of microglial cells by PrP106-126 results in elevated intracellular Ca 2ϩ levels through L-type voltage-sensitive Ca channels, which subsequently produces neurodegeneration.…”

Section: )mentioning

confidence: 99%