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The Journal of Neuroscience, September 14, 2005, 25(37):8451-8456; doi:10.1523/JNEUROSCI.2349-05.2005

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Neurobiology of Disease
Inhibitors of the Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Pathway Clear Prion-Infected Cells from PrP^Sc

Elin K. Nordström, Katarina M. Luhr, Carlos Ibáñez, and Krister Kristensson

Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Prions represent a unique class of infectious agents in which the normal cellular prion protein (PrP^C) is converted to an abnormal isoform (PrP^Sc), which accumulates in the brain and constitutes the major, if not the only, component of the infectious particle. Factors that still remain to be identified may facilitate the conversion of PrP^C to PrP^Sc. In the present study, we first demonstrated that a growth factor of the neurotrophin family, brain-derived neurotrophic factor (BDNF), stimulates the formation of PrP^Sc in a gonadotropin-releasing hormone-secreting neuronal cell line (GT1-1 cells) infected with the Rocky Mountain Laboratory (RML) strain of scrapie as determined by Western blot analysis. We then observed that the prion-infected cells can be cleared from PrP^Sc by treatment with three inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene and 2-(2-amino-3-methyoxyphenyl)-4H-1-benzopyran-4-one, as well as -[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl) benzeneacetonitrile, which passes the blood–brain barrier], a component of one of the intracellular signaling pathways activated by BDNF. The MEK1/2 inhibitors were also efficient in clearing PrP^Sc from prion-infected GT1-1 cells stimulated to accumulate high levels of PrP^Sc by enhanced serum concentrations in the medium or by the use of a serum-free neuron-specific neurobasal medium. PrP^Sc did not reappear in the cultures within 5 weeks after completion of treatment. We conclude that inhibitors of the MEK1/2 pathway can efficiently and probably irreversibly clear PrP^Sc from prion-infected cells. The MEK pathway may therefore be a suitable target for therapeutic intervention in prion diseases.

Key words: prions; MEK inhibitors; growth factors; BDNF; neurons; MAP kinases

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Received June 8, 2005; revised July 15, 2005; accepted July 28, 2005.

This article has been cited by other articles:

				K. Qin, L. Zhao, R. D. Ash, W. F. McDonough, and R. Y. Zhao ATM-mediated Transcriptional Elevation of Prion in Response to Copper-induced Oxidative Stress J. Biol. Chem., February 13, 2009; 284(7): 4582 - 4593. [Abstract] [Full Text] [PDF]

				E. Nordstrom, G. Fisone, and K. Kristensson Opposing effects of ERK and p38-JNK MAP kinase pathways on formation of prions in GT1-1 cells FASEB J, February 1, 2009; 23(2): 613 - 622. [Abstract] [Full Text] [PDF]

				C. R Trevitt and J. Collinge A systematic review of prion therapeutics in experimental models Brain, September 1, 2006; 129(9): 2241 - 2265. [Abstract] [Full Text] [PDF]

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