Local translation is engaged to sustain circuit integrity in severed preserved axonal and synaptic projections

Abstract

AbstractAfter injury, the axon separated from the soma activates programmed axon degeneration, an evolutionarily conserved pathway to initiate its degeneration within a day. However, in various species, severed axonal and synaptic (anucleate) projections remain preserved for weeks to months after injury. How they preserve themselves remains currently unknown. Here, we demonstrate that dNmnat-mediated over-expression attenuates programmed axon degeneration in distinct neuronal populations. These anucleate projections remain morphologically preserved for weeks after injury. When evoked, they elicit a postsynaptic behavior, which we refer to as preserved circuit integrity. We used ribosomal pulldown to isolate translatomes from these anucleate projections. Transcriptional profiling revealed several enriched biological classes. Identified candidates were validated by a novel system to automatically quantify evoked antennal grooming behavior as a proxy for preserved circuit integrity. We used RNAi-mediated knock-down to identify mTOR as a mediator of local protein synthesis, and specifically candidates involved in protein ubiquitination and calcium homeostasis, required for the preservation of circuit integrity. Our dataset uncovered several uncharacterized genes linked to human diseases. It may therefore offer insights into novel avenues for therapeutic treatments.