Editors' ChoicePrions

Toxic Proteins

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Science's STKE  17 Jul 2001:
Vol. 2001, Issue 91, pp. tw7
DOI: 10.1126/stke.2001.91.tw7

Prions are proteins that can produce transmissible neurodegenerative diseases in humans, sheep, goats, and cows. Fabrizi et al. provide a potential mechanism by which misfolding might lead from prion misfolding to activation of microglial cells and to the production of large amounts of nitric oxide, which are believed to be neurotoxic and part of the prion disease progression. Fabrizi et al. treated microglial cells in culture with the synthetic human prion protein fragment (PrP106-126), which reproduces many of the characteristics of the native misfolded prion protein, and determined that the cells were stimulated to secrete tumor necrosis factor α (TNF-α) and to express nitric oxide synthase II (NOS II), producing high levels of nitrite. Blocking the activity of the secreted TNF-α with an antibody resulted in the loss of the induction of NOS II expression in response to PrP106-126. PrP106-126 treatment led to the activation of nuclear factor NF-κB, a known transcriptional activator of TNF-α. Inhibition of NF-κB activation and TNF-α secretion could be achieved by treating the cells with a selective p38 mitogen-activated protein kinase inhibitor. Thus, prion proteins appear to activate the p38 stress pathway resulting in activation of NF-κB, which stimulates TNF-α expression, which in turn stimulates NOS II expression, leading to the production of toxic reactive nitrogen radicals, which may contribute to the cytotoxicity of the misfolded prion.

C. Fabrizi, V. Silei, M. Menegazzi, M. Salmona, O. Bugiani, F. Tagliavini, H. Suzuki, G. M. Lauro, 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 a p38 mitogen-activated protein kinase. J. Biol. Chem. 276, 25692-25696 (2001). [Abstract] [Full Text]

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