Local translation is required for sustained circuit integrity in impaired Wallerian degeneration

Abstract After injury, the axon separated from the soma activates an evolutionarily conserved pathway to initiate its degeneration within a day. Attenuation of this pathway results in morphologically preserved severed axons and synapses for weeks after injury. When evoked, these projections remain able to elicit a postsynaptic behavior, a phenomenon that we define as preserved circuit integrity. The mechanism enabling the preservation of circuit integrity is currently unknown. Here we demonstrate that dNmnat-mediated over-expression potently blocks programmed axon degeneration in Drosophila . Thus, severed axons and their synapses of distinct sensory neuron populations remain morphologically preserved and circuit-integrated for at least a week. We used ribosomal pulldown to isolate translatomes from these severed projections. Transcriptional profiling revealed several enriched biological classes. Identified candidates were assessed by the quantification of evoked antennal grooming behavior as proxy for preserved circuit integrity. We identified mediators of local protein synthesis, and specifically candidates involved in protein ubiquitination and calcium homeostasis required for the preservation of circuit integrity by RNAi-mediated knock-down. Our dataset uncovered several uncharacterized genes linked to human disease and may therefore offer insights into avenues for therapeutic treatments.