An Ionic Sensor acts in Parallel to dSarm to Promote Neurodegeneration.

How neurons to sense when they are terminally dysfunctional and activate neurodegeneration remains poorly defined. The pro-degenerative NAD hydrolase dSarm/SARM1 can act as a metabolic sensor by detecting pathological changes in NAD /NMN and subsequently induce catastrophic axon degeneration. Here we show with-no-lysine kinase (dWnk), which can directly sense Cl , K and osmotic pressure, is required for neurodegeneration induced by depletion of the NAD biosynthetic enzyme dNmnat. dWnk functions in parallel to dSarm and acts through the downstream kinase Frayed to promote axon degeneration and neuronal cell death. dWnk and dSarm ultimately converge on the BTB-Back domain molecule Axundead (Axed) to execute neurodegeneration. Our work argues that neurons use direct sensors of both metabolism (dSarm/SARM1) and ionic/osmotic status (dWnk) to evaluate cellular health and, when dysfunctional, promote neurodegeneration though a common axon death signaling molecule, Axundead.