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Prion Formation Correlates With Activation of Translation-Regulating Protein 4E-BP and Neuronal Transcription Factor Elk1

Prion Formation Correlates With Activation of Translation-Regulating Protein 4E-BP and Neuronal Transcription Factor Elk1

Elin K Allard, Mirjana Grujic, Gilberto Fisone, Krister Kristensson

Neurobiol Dis. 2013 Oct;58:116-22.

PMID: 23742760

Abstract:

Cellular mechanisms play a role in conversion of the normal prion protein PrP(C) to the disease-associated protein PrP(Sc). The cells provide not only PrP(C), but also still largely undefined factors required for efficient prion replication. Previously, we have observed that interference with ERK and p38-JNK MAP kinase pathways has opposing effects on the formation of prions indicating that the process is regulated by a balance in intracellualar signaling pathways. In order to obtain a "flow-chart" of such pathways, we here studied the activation of MEK/ERK and mTORC1 downstream targets in relation to PrP(Sc) accumulation in GT1-1 cells infected with the RML or 22L prion strains. We show that inhibition of mTORC1 with rapamycin causes a reduction of PrP(Sc) accumulation at similar low levels as seen when the interaction between the translation initiation factors eIF4E and eIF4G downstream mTORC1 is inhibited using 4EGI-1. No effect is seen following the inhibition of molecules (S6K1 and Mnk1) that links MEK/ERK signaling to mTORC1-mediated control of translation. Instead, stimulation (high [KCl] or [serum]) or inhibition (MEK-inhibitor) of prion formation is associated with increased or decreased phosphorylation of the neuronal transcription factor Elk1, respectively. This study shows that prion formation can be modulated by translational initiating factors, and suggests that MEK/ERK signaling plays a role in the conversion of PrP(C) to PrP(Sc) via an Elk1-mediated transcriptional control. Altogether, our studies indicate that prion protein conversion is under the control of intracellular signals, which hypothetically, under certain conditions may elicit irreversible responses leading to progressive neurodegenerative diseases.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP24125164	Leupeptin hydrochloride		24125-16-4	Price
AP522629089-A	CGP 57380		522629-08-9	Price

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