Disruption of G3BP1 granules promotes mammalian CNS and PNS axon regeneration

PNAS, 2025 · DOI: https://doi.org/10.1073/pnas.2411811122 · Published: February 27, 2025

Regenerative Medicine Neurology Genetics

Simple Explanation

The central nervous system (CNS) axon does not have the capacity for spontaneous axon regeneration, as seen in the peripheral nervous system (PNS). CNS axons contain G3BP1 granules, and G3BP1 granule disassembling strategies promote axon regeneration in the injured sciatic nerve, transected spinal cord with a peripheral nerve graft, and injured optic nerve. G3BP1 granules are a barrier to axon regeneration and can be targeted for stimulating neural repair following traumatic injury, including in the regeneration refractory CNS.

Study Duration

Not specified

Participants

Sprague Dawley rats and wild type 129s mice

Evidence Level

Not specified

Key Findings

1
G3BP1 B-domain expression was found to promote axon regeneration in the transected spinal cord provided with a permissive peripheral nerve graft (PNG) as well as in crushed optic nerve.
2
A cell-permeable peptide (CPP) to a subregion of B-domain (rodent G3BP1 amino acids 190 to 208) accelerated axon regeneration after peripheral nerve injury and promoted regrowth of reticulospinal axons into the distal transected spinal cord through a bridging PNG.
3
The G3BP1 CPP disassembles axonal G3BP1, G3BP2, and FMRP, but not FXR1, granules and selectively increases axonal protein synthesis in cortical neurons.

Research Summary

We previously showed that decreasing LLPS of RNA–protein granules containing the core stress granule protein G3BP1 accelerates the regeneration of injured PNS axons. Expression of G3BP1’s conserved B-domain (amino acids 141 to 220) accelerates regeneration of reticulospinal axons in the growth-permissive environment of a peripheral nerve grafted into the hemisected spinal cord and is sufficient to enable injured RGCs to regenerate axons in the growth-inhibitory CNS environment of the injured optic nerve. G3BP1 190-208 CPP strategy used here is effective when delivered 2 d after PNS injury and at least 30 d after spinal cord injury, which elevates the potential clinical relevance of these reagents for neural repair treatments.

Practical Implications

Therapeutic Strategy

G3BP1 granule disassembly can serve as a potential therapeutic strategy for enhancing axon growth and neural repair.

Clinical Relevance

The G3BP1 190-208 CPP strategy is effective when delivered after PNS and spinal cord injury, increasing its clinical potential.

Further Research

Structure-activity relationship studies point to alternating acidic residue and Pro repeats as the functional component, presenting opportunities for further refinement of CPP activity.

Study Limitations

1
The mechanism by which G3BP1 B-domain and 190-208 CPP disrupt G3BP1 granules is not yet clear.
2
The study acknowledges that the G3BP1 190-208 CPP activity has a limited in vivo duration, emphasizing an opportunity to improve peptide stability.
3
Successful long-distance CNS axon regeneration with G3BP1 granule inhibition may require simultaneous inhibition of RhoA.

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