Very little is known about the role of peripheral glia contacting axons or the nerve terminal. In mammals, the proinflammatory cytokine TNF-α is expressed in Schwann cells and has been implicated in the mechanisms of demyelination during multiple sclerosis (Qin et al., 2008). However, the involvement of TNF-α in ALS remains controversial. TNF-α knockout mice are viable, and elimination of TNF-α did not protect motoneurons from degeneration following overexpression of mutant SOD1 in mouse motoneurons (Gowing et al., 2006). It is worth noting that a compensatory upregulation of related proinflammatory cytokines, IL-1-β and TLR-2, was

observed, and this could reasonably account for the failure of the TNF-α knockout to protect against SOD1 mediated motoneuron degeneration Z-VAD-FMK nmr (Gowing et al., 2006). We previously established a system to study motoneuron degeneration in Drosophila. In Drosophila, genetic lesions in the dynein dynactin complex ( Eaton et al.,

2002) and the spectrin/ankyrin skeleton ( Pielage et al., 2005, Pielage et al., 2008, Pielage et al., 2011 and Massaro et al., 2009) disrupt axonal transport and cause degeneration of the neuromuscular junction (NMJ) and motor axons. Motoneuron degeneration in Drosophila shares many of the cellular hallmarks of degeneration in mammalian neurons, observed at the light level, ultrastructurally and electrophysiologically. Genetic lesions in dynactin and the spectrin/ankyrin skeleton cause ALS and spinal cerebellar ataxia type 5 (SCA5) in humans ( Puls et al., 2003 and Ikeda et al., 2006). Mouse and Drosophila models of these diseases employing similar genetic lesions have UMI-77 nmr been developed ( LaMonte et al., 2002 and Lorenzo et al., 2010). Taken together, these data imply that common cellular stresses are able to initiate motoneuron Chlormezanone degeneration in insects and mammals. Furthermore, motoneuron

degeneration in Drosophila can be suppressed by expression of a wallerian degeneration slow (WldS) transgene, implying the existence of common degenerative signaling pathways in mammalian and fly neuromuscular systems ( Massaro et al., 2009). Taking advantage of an in vivo model system for motoneuron degeneration in Drosophila, we now provide evidence for a prodegenerative-signaling pathway that originates within the motoneuron and passages through the peripheral glia that are in close proximity to the motoneuron axon. We present evidence that TNF-α, expressed in a subset of peripheral glia, acts via a conserved TNF-α receptor (TNFR), expressed in motoneurons, to initiate prodegenerative signaling within the motor axon. The prodegenerative-signaling pathway is genetically independent of c-Jun N-terminal kinase (JNK) and NFκβ, two prominent pathways that reside downstream of the TNFR. Instead, we show that the prodegenerative process requires the Drosophila effector caspase, Dcp-1, which we demonstrate is both necessary and sufficient for motoneuron degeneration.