Molecular Mechanisms of Axon Degeneration. Marc R. Freeman. Dept Neurobiology, Univ Massachusetts Med Sch/HHMI, Worcester, MA.

   Widespread axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axon degeneration has been proposed to be mediated by an active auto-destruction program, akin to apoptotic cell death, however loss of function mutations capable of potently blocking axon self-destruction remain poorly defined. We are using simple axotomy models in combination with forward genetic screening approaches in Drosophila to explore the molecular and cellular basis of axon degeneration. We recently discovered the Drosophila Toll receptor adaptor dSarm (sterile /Armadillo/Toll-Interleukin receptor homology domain protein) promotes axon destruction, and that loss of dSarm function can cell-autonomously suppress the degeneration of severed axons for the lifespan of the fly. Notably, dSarm is dispensable for developmental neurite pruning and caspase-dependent cell death in Drosophila, indicating these events are mediated by distinct genetic programs. We have further shown that pro-degenerative Sarm1 function is conserved in mice, where transected Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro. Our results provide direct evidence that axons actively promote their own destruction after injury and identifies dSarm/Sarm1 as a founding member of an ancient axon death signaling pathway.