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bioRxiv · 10.1101/2023.08.18.553870

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

Paglione, M.·Restivo, L.·Zakhia, S.·Llobet Rosell, A.·Terenzio, M.·Neukomm, L. J.
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Abstract

After injury, the severed axon separated from the soma activates programmed axon degeneration, an evolutionarily conserved pathway to initiate its degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after injury. How this synaptic function is sustained remains currently unknown. Here, we demonstrate that dNmnat-mediated over-expression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks after injury. When evoked, they elicit a postsynaptic behavior which is a readout for preserved synaptic function. We used ribosomal pulldown to isolate translatomes from these projections. Transcriptional profiling revealed several enriched biological classes. Identified candidates were validated in a screen using a novel system to automatically quantify evoked antennal grooming behavior as a proxy for preserved synaptic function. We used RNAi-mediated knockdown to identify mTOR as a mediator of local protein synthesis, and specifically candidates involved in protein ubiquitination and calcium homeostasis, required for preserved synaptic function. Our dataset uncovered several uncharacterized genes linked to human diseases. It may therefore offer insights into novel avenues for therapeutic treatments.

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Paglione, M., Restivo, L., Zakhia, S., Llobet Rosell, A., Terenzio, M., Neukomm, L. J.. 2023-08-20. Local translation is required for sustained circuit integrity in impaired Wallerian degeneration. https://doi.org/10.1101/2023.08.18.553870

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