Locally translated mTOR controls axonal local translation in nerve injury

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Neuronal injury triggers complex cellular responses, including changes in protein synthesis.
• Local protein synthesis within axons is essential for neuronal repair and survival.
• The role of mechanistic target of rapamycin (mTOR) in axonal protein synthesis and injury response is not fully understood.

Purpose of the Study:

• To investigate the mechanisms of local protein synthesis initiation in injured axons.
• To determine the role of mechanistic target of rapamycin (mTOR) in regulating local translation within axons.
• To elucidate the contribution of mRNA localization to axonal repair and neuronal survival.

Main Methods:

• Utilized mouse models with targeted deletion of the mTOR 3' untranslated region (3'UTR).
• Employed pharmacological inhibition of mTOR in axons.
• Investigated the transport of mTOR mRNA into axons via nucleolin.
• Assessed protein levels of mTOR, importin β1, and STAT3 in injured axons.

Main Results:

• mTOR (mechanistic target of rapamycin) is activated and upregulated in injured axons via local mTOR mRNA translation.
• Nucleolin facilitates the axonal transport of mTOR mRNA.
• mTOR regulates its own translation and that of retrograde injury signaling molecules (importin β1, STAT3).
• Deletion of mTOR 3'UTR or pharmacological inhibition of axonal mTOR reduces local translation and neuronal survival after nerve injury.

Conclusions:

• mRNA localization provides spatiotemporal control over mTOR pathways, governing local translation and intracellular signaling.
• Local mTOR activation is critical for axonal repair and the survival of proprioceptive neurons following nerve injury.
• Targeting local protein synthesis pathways offers potential therapeutic strategies for neuronal injury.