In light of these data and of our previous studies8,9, we propose a pathogenic model of neurodegeneration in ALS in which astrocyte-specific release of a soluble fragment of APP, and possibly of other ligands prioritized by our analysis, activates DR6 at the surface of MNs, thus triggering a death signal that culminates in the demise of spinal MNs via NF-κB1-dependent pathway. Here, TNFRSF21 is linked to amyotrophic lateral sclerosis.