Disruption of G3BP1 Granules Promotes Mammalian CNS and PNS Axon Regeneration

Neurology Neurosurgery Medicine Life Sciences Cell Biology
axon regeneration central nervous system G3BP1 granules peripheral nervous system neural repair

Academic Background

The regenerative capacity of the nervous system varies significantly between different regions. Axons in the peripheral nervous system (PNS) can regenerate spontaneously after injury, whereas axons in the central nervous system (CNS) lack this ability. This difference makes recovery after CNS injury extremely challenging, especially for spinal cord and optic nerve injuries. Although PNS axons are capable of regeneration, their regeneration rate is very slow, typically 1 to 4 millimeters per day, and the success rate of long-distance regeneration is extremely low. Therefore, how to accelerate PNS axon regeneration and promote CNS axon regeneration has been a significant challenge in the field of neuroscience.

Previous studies have shown that G3BP1 (Ras GTPase-activating protein SH3 domain-binding protein 1) forms stress granules in PNS axons and slows axon regeneration by sequestering mRNA. Based on this finding, researchers hypothesized that G3BP1 granules might also be a barrier to CNS axon regeneration. Thus, they hoped to explore the potential role of disrupting G3BP1 granules in CNS and PNS axon regeneration and find new strategies to promote neural regeneration.

Paper Source

This paper was jointly completed by multiple researchers including Pabitra K. Sahoo, from several renowned institutions, including the University of South Carolina, Rutgers University, Boston Children’s Hospital, Emory University, etc. The paper was published in the journal PNAS (Proceedings of the National Academy of Sciences) on February 27, 2025, titled “Disruption of G3BP1 granules promotes mammalian CNS and PNS axon regeneration.”

Research Process and Results

Research Process

  1. Presence of G3BP1 Granules in CNS Axons and Their Impact on Regeneration

The researchers first detected the presence of G3BP1 granules in undamaged CNS axons using immunofluorescence techniques. They found that G3BP1 granules indeed exist in CNS axons and increase significantly after injury. To verify whether G3BP1 granules impede axon regeneration, the researchers expressed the acidic domain (b-domain) of G3BP1 through viral vectors in a spinal cord injury model and observed its impact on axon regeneration.

  1. Expression of G3BP1 b-domain Promotes CNS Axon Regeneration

In the spinal cord injury model, the researchers implanted a peripheral nerve graft (PNG) at the injury site to provide an environment conducive to axon growth. After expressing the G3BP1 b-domain via a viral vector, the researchers found a significant increase in axon regeneration, particularly in the extension distance of axons within the grafts.

  1. G3BP1 Cell-Permeable Peptide (CPP) Promotes PNS Axon Regeneration

To further validate the effect of G3BP1 b-domain, the researchers designed a cell-permeable peptide (CPP) and tested its efficacy in a PNS injury model. By directly injecting the CPP into the injured sciatic nerve site, the researchers observed a significant acceleration in axon regeneration and a noticeable increase in the speed of neuromuscular junction reinnervation.

  1. Effect of G3BP1 CPP in CNS

In the spinal cord injury model, the researchers injected G3BP1 CPP into the injury site and observed its impact on axon regeneration. The results showed that G3BP1 CPP played a positive role in axon regeneration after spinal cord injury, with a significant increase in axonal branching within the peripheral nerve graft.

  1. Regulation of Axonal Protein Synthesis by G3BP1 CPP

The researchers further explored the mechanism of action of G3BP1 CPP and found that it could disrupt G3BP1 granules in axons and selectively increase axonal protein synthesis. This discovery suggests that the disruption of G3BP1 granules may promote the synthesis of proteins related to axon regeneration by releasing sequestered mRNAs.

Main Results

  1. Presence of G3BP1 Granules in CNS Axons
    The researchers confirmed through immunofluorescence techniques that G3BP1 granules exist in CNS axons and significantly increase after injury.

  2. Promotion of CNS Axon Regeneration by G3BP1 b-domain
    In the spinal cord injury model, expressing G3BP1 b-domain significantly increased axon regeneration, especially the extension distance of axons within the peripheral nerve grafts.

  3. Promotion of PNS Axon Regeneration by G3BP1 CPP
    In the sciatic nerve injury model, G3BP1 CPP significantly accelerated axon regeneration and promoted the reinnervation of neuromuscular junctions.

  4. Effect of G3BP1 CPP in CNS
    In the spinal cord injury model, G3BP1 CPP significantly increased axonal branching, especially within the peripheral nerve graft.

  5. Regulation of Axonal Protein Synthesis by G3BP1 CPP
    G3BP1 CPP could disrupt G3BP1 granules in axons and selectively increase axonal protein synthesis, indicating that it promotes axon regeneration by releasing sequestered mRNAs.

Conclusion and Significance

This study shows that G3BP1 granules are key barriers to CNS and PNS axon regeneration, and disrupting these granules can significantly promote axon regeneration. By expressing G3BP1 b-domain or using G3BP1 CPP, the researchers successfully accelerated axon regeneration after spinal cord and optic nerve injuries. This discovery provides new strategies for treating nerve injuries, especially bringing hope for neural repair after CNS injuries.

Highlights of the Study

  1. Presence of G3BP1 Granules in CNS Axons
    This discovery confirms for the first time the presence of G3BP1 granules in CNS axons and reveals their mechanism in impeding axon regeneration.

  2. Application of G3BP1 b-domain and CPP
    By expressing G3BP1 b-domain or using G3BP1 CPP, the researchers successfully promoted CNS and PNS axon regeneration, providing new tools for treating nerve injuries.

  3. Regulation of Axonal Protein Synthesis
    The researchers revealed the mechanism by which G3BP1 granules inhibit axon regeneration by sequestering mRNA and demonstrated that disrupting these granules increases axonal protein synthesis, promoting regeneration.

Other Valuable Information

The study also explored the effects of G3BP1 CPP in different growth environments, finding that it promotes axon elongation in permissive environments and increases axon branching in inhibitory environments. This finding provides a new perspective for understanding the regulatory mechanisms of axon regeneration.

This research not only reveals the important role of G3BP1 granules in axon regeneration but also provides new strategies for treating nerve injuries, holding significant scientific and application value.