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Local translatome sustains synaptic function in impaired Wallerian degeneration

ABSTRACT: After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat over-expression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections one week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of mTOR, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.

SUBMITTER: Dr. Maria Paglione

PROVIDER: S-SCDT-10_1038-S44319-024-00301-8 | biostudies-other |

REPOSITORIES: biostudies-other

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Local translation is engaged to sustain synaptic function in impaired Wallerian degeneration

Project description:After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their 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. 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 automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. We used RNAi-mediated knockdown to identify mTOR as a mediator of protein synthesis, and 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 offer insights into novel avenues for therapeutic treatments.

2024-10-24 | GSE270011 | GEO

Local translation is engaged to sustain synaptic function in impaired Wallerian degeneration

Project description:Local translation is engaged to sustain synaptic function in impaired Wallerian degeneration

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