神经损伤与修复
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Figure 1｜Model of the mechanism of p75-CTF induced cell death.
The proteolysis of p75NTR has been suggested important for its pro-apoptotic activity. Recently, the increased levels of the p75-CTF in hippocampal and cerebral neurons by the use of γ-secretase inhibitors showed an increase in cell death in those neuronal populations (Vicario et al., 2015). A similar result was described earlier in sensory neurons (Underwood et al., 2008). The consequence of the inhibition of the γ-secretase complex on the BFCNs was studied recently in our labratory (Franco et al., 2021). The outcome was quite different from hippocampal and cereberal neurons, in the sense that the inhibition of the γ-secretase with GSIs, although it increased the levels of p75-CTF, does not induce cell death of the BFCNs. In the search for the mechanism of this result, we choose the cell lines PC12 cells (that express both p75 and TrkA) and a specific clone PC12-nnr5 cells (that express p75 but not TrkA). We found that GSIs induced the cell death of PC12nnr5 cells, and not PC12, indicating that TrkA activation may have a role in the survival of BFCNs. Actually when the primary cultures of BFCNs are incubated with GSIs plus a TrkA kinase inhibitor there was a significant cell death (Franco et al., 2021). This result suggests that the formation of p75-CTF per se is not indicative of a pro-death signal if TrkA is active, and that in the absence of TrkA signaling, p75-CTF is able to trigger cell death. The molecular mechanism proposed suggests that in the presence of GSIs, the levels of p75-CTF increased at the plasma membrane inducing its oligomerization and causing cell death by activation of TRAF6 and JNK/p38 pathways (Frgure 1).