Developmentally regulated changes in c-Jun N-terminal kinase signalling determine the apoptotic response of oligodendrocyte lineage cells

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Our findings reinforce the strong link between JNK activation and phosphorylation of the transcription factor c-Jun, which has been implicated in neuronal cell death.¹⁵ In naïve OPC, we found that the kinetics of c-Jun phosphorylation correlated closely with JNK activation and apoptosis (Figure 1d and f). In contrast, in ceramide-induced apoptosis of mature OL, we found only low levels of phospho-Jun protein and the absence of JNK activity, suggesting that this pathway is not involved in the ceramide stress response (Figure 1e). This is in accord with a previous report that dominant-negative c-Jun does not attenuate ceramide-induced OL cell death.¹⁶ To determine whether the JNK pathway is required for apoptosis of OL lineage cells, we employed D-JNKI, a pharmacological inhibitor of JNK activity based on the binding domain of c-Jun interactive protein-1. D-JNKI is highly cell-permeable and acts as a decoy substrate, potently and selectively inhibiting all JNK isoforms.¹⁷ While D-JNKI effectively blocked both JNK activity and c-Jun phosphorylation in naïve OPC exposed to UV, it only partially protected against apoptosis while there was no reduction in SSP toxicity (Figure 2d). It has been similarly shown that mutation of the JNK phosphorylation sites in c-Jun leads to partial protection against UV-induced cell death.¹⁸ One possibility for this apparent paradox may be that some JNK family members may be important for cell survival and so blocking all JNK isoforms may result in cell death, depending on the balance of the signalling pathways. Therefore, the selective inhibition of JNK3 may be more relevant to reducing OL or neuronal cell death following injury. We are currently adopting an RNAi approach to investigate the effects of selectively reducing JNK3 expression.

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