Local translatome sustains synaptic function in impaired Wallerian degeneration

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Axons undergo programmed degeneration after injury, limiting their regenerative potential.
• Severed axons lacking this degeneration pathway can remain functional for extended periods, but the mechanisms are unclear.

Purpose of the Study:

• To investigate how severed axons maintain synaptic function long-term.
• To identify molecular mechanisms sustaining functional synapses after axotomy.

Main Methods:

• Overexpression of dNmnat to attenuate programmed axon degeneration.
• Ribosomal pulldown to isolate and analyze the translatome of severed axons.
• Automated system for detecting evoked antennal grooming as a proxy for synaptic function.
• RNAi-mediated knockdown to identify essential genes.

Main Results:

• dNmnat overexpression preserved severed axons morphologically and functionally for weeks.
• Translatome analysis revealed enrichment in protein synthesis and homeostasis pathways.
• mTORC1 pathway components, protein ubiquitination, and Ca2+ homeostasis genes were required for sustained synaptic function.

Conclusions:

• Programmed axon degeneration can be attenuated, preserving axonal structure and synaptic function.
• Sustained synaptic function relies on active molecular processes including protein synthesis and homeostasis.
• Identified novel genes, including uncharacterized Drosophila genes linked to human diseases, offering therapeutic insights.