Inhibitors of the Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Pathway Clear Prion-Infected Cells from PrP<sup>Sc</sup>

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

doi:10.1523/jneurosci.2349-05.2005

Cited by 23 publications

(17 citation statements)

References 42 publications

(51 reference statements)

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“…In addition, considering the protective activity of PrP C against oxidative stress, prion replication might also subtract an important ROS buffer from the cell, as proved by the augmented susceptibility of PrP C -deficient cells to oxidants [74]. Notably, pharmacological inhibitors of ERK phosphorylation were shown to clear PrP Sc from prion-infected cells [75], suggesting a direct role for the ERK pathway in prion formation. By contrast, Uppington et al [76] and suggested that the increased activity of the ERK pathway has a protective role against prion-induced neurotoxicity.…”

Section: Prion Protein and The Src Familymentioning

confidence: 99%

Prion protein and its role in signal transduction

Didonna

2013

Cellular and Molecular Biology Letters

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Prion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their etiologic agent: prions (PrP Sc ). A prion is an infectious protein with the ability to convert the host-encoded cellular prion protein (PrP C ) into new prion molecules by acting as a template. Since Stanley B. Prusiner proposed the "protein-only" hypothesis for the first time, considerable effort has been put into defining the role played by PrP C in neurons. However, its physiological function remains unclear. This review summarizes the major findings that support the involvement of PrP C in signal transduction.

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Section: Prion Protein and The Src Familymentioning

confidence: 99%

Prion protein and its role in signal transduction

Didonna

2013

Cellular and Molecular Biology Letters

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“…Several enzyme and cell signalling inhibitors have been found to have anti-prion abilities, including inhibitors of mitogen-activated protein kinase [170], cysteine-protease [93], phospholipase A 2 and platelet activating factor [171], p53 [172], and tyrosine kinase [173]. The latter, specifically imatinib mesylate, can delay neuroinvasion, possibly through increasing PrP Sc clearance [174].…”

Section: Cell Signalling Pathwaysmentioning

confidence: 99%

Prion Disease: Chemotherapeutic Strategies

Sim

2012

IDDT

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Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. Thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. However, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, including the role of oligomers and the contribution of accessory molecules and signalling cascades, the chance of finding a therapeutic strategy is increasing. Beyond clinical therapy, there is increasing need to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) is transmissible by blood. Non-toxic preventative therapies are also needed, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD) being a growing concern. A primary target for therapy has been the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPSc). Many of the chemotherapeutic agents with antiprion effect share structural similarities, often being polyanionic or polycyclic. They may directly bind PrPC or PrPSc, or they may redistribute, sequester, or down-regulate PrPC, thus preventing its conversion. There have also been some novel approaches, including trapping PrPSc in a multimeric form such that it can no longer cause conversion, increasing clearance of PrPSc, targeting accessory molecules which play a role in conversion, targeting pathways which lead to neurodegeneration, and stem cell therapy. It may be that a combination of compounds will be necessary for maximal effect and there is evidence that synergistic responses occur with dual therapy. This updated review focuses primarily on chemicalbased treatments in light of developments in diagnostic technologies, including results from recent clinical trials, and proposes some promising new targets for prion therapy.

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“…SL327, through inhibition of MEK½, decreased PrP res in cells [207]. Given its ability to cross the blood-brain barrier, SL327 might have some in vivo effects, although no in vivo data are currently available.…”

Section: Targeting Intracellular Enzymes and Pathways Involved In Prpmentioning

confidence: 99%