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  4. Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar

Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar

The Journal of Neuroscience, 2015 · DOI: 10.1523/JNEUROSCI.0719-15.2015 · Published: August 5, 2015

Spinal Cord InjuryRegenerative MedicineGenetics

Simple Explanation

After a spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to the diminished growth capacity of adult neurons and the presence of inhibitory molecules in the scar at the lesion. The researchers aimed to overcome these obstacles by enhancing the intrinsic growth potential of neurons and modifying the inhibitory glial scar. They used a constitutively active form of Rheb (caRheb) to stimulate neuronal growth and chondroitinase ABC (ChABC) to digest inhibitory molecules in the scar. The study found that combining caRheb expression with ChABC treatment significantly improved axon regeneration beyond the injury site, suggesting that addressing both intrinsic and extrinsic factors is crucial for successful SCI repair.

Study Duration
3 Months
Participants
Adult female Wistar rats (225–250 g weight)
Evidence Level
Not specified

Key Findings

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    CaRheb expression promotes growth of axons into a peripheral nerve graft (PNG).
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    Combining caRheb expression in neurons and ChABC treatment of the glial scar enhances axon growth beyond a PNG.
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    Regenerating axons form putative synapses, suggesting the potential for functional recovery.

Research Summary

This study investigates whether expressing a constitutively active form of Rheb (caRheb) in adult neurons after a complete spinal cord injury (SCI) in rats improves intrinsic growth potential and results in axon regeneration out of a growth-supportive peripheral nerve graft (PNG) into the SCI cavity. The researchers hypothesized that treating the glial scar with chondroitinase ABC (ChABC), which digests CSPGs, would further allow caRheb-transduced neurons to extend axons across the distal graft interface. The study demonstrates that simultaneously addressing neuron-related, intrinsic deficits in axon regrowth and extrinsic, scar-associated impediments to regeneration results in significant regeneration after SCI.

Practical Implications

Therapeutic Potential

The combination of caRheb and ChABC could be a potential therapeutic strategy for promoting axon regeneration after spinal cord injury.

Understanding Regeneration

The study provides insights into the mechanisms underlying axon regeneration and the importance of targeting both intrinsic and extrinsic factors.

Clinical Relevance

Targeting the mTOR pathway at a clinically relevant post-SCI time point improves both sprouting and regeneration of axons.

Study Limitations

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