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Harvard Medical School
I think this is an interesting study, as it provides new insights into the mechanism of MN death in ALS. That almost all of the 11 regulators identified are transcription factors suggests that the death of MN involves transcription. These regulators overlap with the necroptosis factors identified in our genome-wide siRNA screen for genes involved in mediating necroptosis of L929 cells stimulated by zVAD.fmk, which inhibits caspase activation. Since zVAD-induced necroptosis of L929 cells involves transcription and translation of pro-inflammatory factor TNFα, we might consider the possibility that autocrine production of some pro-death factors is also involved in MN death in this model.
NF-κB is known to be pro-inflammatory and inflammatory cytokines, such as TNFα, have well-established roles in promoting cell death; thus, autocrine production of pro-inflammatory cytokines mediated by these transcriptional factors that lead to necroptosis of MNs would be consistent with the existing knowledge about the pro-inflammatory role of NF-κB.
We still need to validate these studies in vivo, e.g., in animal models and in human ALS. We also do not know what the upstream activators of these transcriptional factors are, nor the downstream mediators to lead to necroptosis.
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