Figure 9. Summary and Model.

(A) Summary of genetic data in support of prodegenerative-signaling pathways. (1) The loss of either Eiger within peripheral glia or the loss of Wengen within motoneurons suppresses ankyrin-dependent neuromuscular degeneration (neuronal stress) at the Drosophila NMJ. Based on these data, we propose that Eiger and Wengen establish a glial-derived, prodegenerative-signaling system. (2) Expression of either the initiator caspase Dronc or the effector caspase Dcp-1 is sufficient to cause synaptic degeneration at the NMJ. Additionally, Dcp-1 is necessary for prodegenerative signaling. Based on these data, we propose the involvement of a caspase-signaling system that is activated following disruption of the spectrin/ankyrin skeleton. (3) Mitochondria-dependent signaling (mito) participates in the neurodegenerative-signaling system at the Drosophila NMJ. A mutation in miro (not shown), which depletes mito-chondria from motor axons and synapses, significantly suppresses degeneration. Additionally, mutations in two genes, debcl and dark, previously shown to function downstream of disrupted mitochondria in other systems, suppress degeneration. Therefore, we propose the involvement of a mitochondria-dependent signaling system in the degenerative response.

(B) Proposed model for glial-derived prodegenerative signaling in Drosophila motoneurons. According to this model, a neuronal stress such as disruption of the spectrin/ankyrin skeleton is detected by surrounding peripheral glia, which respond by release of Eiger (TNF-α). Eiger is detected by Wengen (TNFR) in motoneurons and may lead to downstream caspase activation followed by disassembly of the motor axon and/or synapse. We also propose involvement of a mitochondrial-dependent signaling system involving Debcl and Dark that may function to potentiate the prodegenerative caspase response. Notably, there may be direct signaling from a site of axonal stress to activation of mitochondria-dependent degenerative signaling.