Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Cells, 2021 · DOI: https://doi.org/10.3390/ cells10112942 · Published: October 29, 2021

Simple Explanation

Following spinal cord injury, astrocytes, a type of brain cell, can either help or hinder recovery. This study focuses on Transglutaminase 2 (TG2), a protein that affects how astrocytes respond to injury. The researchers found that by either deleting TG2 in astrocytes or inhibiting its activity with a drug, mice with spinal cord injuries showed significant improvements in motor function. This suggests that targeting TG2 could be a new way to treat spinal cord injuries and other CNS injuries, helping astrocytes to support recovery rather than inhibit it.

Study Duration

42 days

Participants

TG2-A-cKO and TG2fl/fl mice

Evidence Level

Not specified

Key Findings

1
Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI.
2
GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice.
3
Treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI.

Research Summary

The study investigates the role of transglutaminase 2 (TG2) in astrocytes following spinal cord injury (SCI) using a mouse model with astrocyte-specific TG2 deletion (TG2-A-cKO). Deletion of TG2 in astrocytes led to significant improvements in motor function recovery after SCI, accompanied by reduced GFAP and NG2 immunoreactivity, as well as a decrease in SOX9 positive cells. Treatment with the TG2 inhibitor VA4 also improved functional recovery after SCI in wild-type mice, suggesting TG2 inhibition as a potential therapeutic strategy for SCI and other CNS injuries.

Practical Implications

Therapeutic Target

TG2 inhibitors may be a therapeutic strategy for treating acute SCI.

Improved Regeneration

Deletion of TG2 from astrocytes results in an environment that is more permissive for successful regeneration following a CNS injury.

Metabolic Coupling

TG2 ablation in astrocytes promotes a more regenerative phenotype.

Study Limitations

1
The direct role of reactive astrocytes in the production of CSPGs remains unclear
2
Whether VA4 is acting locally at the site of injury or alters the injury response through effects in the periphery, or both, remains to be seen.
3
Additional studies will be needed to determine whether the increased expression of genes involved in fatty acid uptake and metabolism contribute to improved recovery in TG2-cKO animals through re-uptake of lipids released post-injury, improved astrocyte–neuron metabolic coupling and/or increased remyelination.

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