Regulation of prion formation by intracellular signalling pathways: possible clues on the fine tuning of prion generation and removal

Cellular mechanisms play a role in conversion of the normal prion protein PrPC to the disease-associated protein PrPSc. The cells provide not only PrPC, but also still largely undefined factors required for efficient prion replication. Work from Priority researchers at the Karolinska Institute in Stockholm, reveals key roles of intracellular signalling pathways in prion formation.


Previously, members of this group, led by Krister Kristensson,  had observed that interference with ERK and p38-JNK MAP kinase pathways has opposing effects on prion formation indicating that the process is regulated by a balance in intracellualar signaling pathways. In order to obtain a “flow-chart” of such pathways, they have studied the activation of MEK/ERK and mTORC1 downstream targets in relation to PrPSc accumulation in GT1-1 cells infected with the RML or 22L prion strains.

These studies have shown that factors involved in PrPSc formation can be translationally modified by the mTORC1/4E-BP downstream pathway following the activation of the eIF4F complex. In addition, the marked MEK/ERK pathway-mediated effects on prion formation are under transcriptional control with the transcription factor Elk1 as a potential candidate (Fig. 1). A dual function of the mTORC1 and MEK/ERK pathways is therefore indicated whereby their activation, which in general is beneficial to the cells, can at the same time promote formation of the pathogen. In Fig. 2 cells are depolarized by high [KCl] and the MEK/ERK inhibitor U0126 (+U) used.

The control of prion formation by opposing intracellular signaling also poses the question whether there exists a balanced state of prion protein conversions that could be reversible. In fact, it has been argued by Prusiner and cols. that PrPC is turned into PrPSc by a random process in which small numbers of prions are cleared via a quality control pathway. How can such a balanced and reversible state be compatible with prion diseases, which once started progresses irreversible to invariable end in fatal neurodegenerative disease?  We speculate that  at some time point under certain conditions the reversible responses may pass through a transition to an irreversible state, as described in other cell biological settings, e.g. in cell division cycle. Knowing intracellular signals governing cell division, the transitions have lend themselves to mathematical modelling by Novak and cols., and, most remarkable, also to interferences that can reverse the irreversible. A long term goal is therefore to understand the transition of a balanced regulation of prion formation to an irreversible process that causes neuronal dysfunctions, and death of the cell and the afflicted individual. Thereby prion studies may disclose cellular mechanisms relevant also for the more common neurodegenerative diseases.


Allard EK, Grujic M, Fisone G, Kristensson K: Prion formation correlates with activation of translation-regulating protein 4E-BP and neuronal transcription factor Elk1 NeuroBiol Dis 58C:116-122, 2013 doi: 10.1016/j.nbd.2013.05.014.

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