Promoting Axon Regeneration in Adult CNS by Targeting Liver Kinase B1

Molecular Therapy, 2019 · DOI: https://doi.org/10.1016/j.ymthe.2018.10.019 · Published: January 1, 2019

Simple Explanation

The study explores promoting axon regeneration in the central nervous system (CNS) by targeting liver kinase B1 (LKB1). LKB1's role in CNS axon regeneration is largely unknown. The researchers overexpressed LKB1 in adult mice after spinal cord injury. Using viral vectors, LKB1 expression was increased in the sensorimotor cortex of adult mice five days post-spinal cord injury. This resulted in dramatically enhanced regeneration of corticospinal axons. Systemic injection of a modified viral vector was also used to upregulate LKB1 specifically in neurons. Upregulating LKB1 improved locomotor functions in adult mice with spinal cord injury. The study suggests LKB1 may be critical for enhancing the growth capacity of mature neurons and a potential target for treating CNS injuries.

Study Duration

8 weeks

Participants

Adult C57BL/6 mice

Evidence Level

Not specified

Key Findings

1
Overexpression of LKB1, delivered via AAV2 viral vector five days post-spinal cord injury, dramatically enhanced regeneration of corticospinal axons in adult mice.
2
Systemic delivery of a mutant AAV9 vector to upregulate LKB1 specifically in neurons promoted long-distance regeneration of injured corticospinal fibers into the caudal spinal cord.
3
Either intracortical or systemic viral delivery of LKB1 significantly improved recovery of locomotor functions in adult mice with spinal cord injury.

Research Summary

This study demonstrates that increasing LKB1 expression in neurons of adult mice, using viral vectors, promotes significant regeneration of corticospinal tract axons after spinal cord injury. The research identifies that LKB1 uses AMPKa, NUAK1, and ERK as downstream effectors in the cortex of adult mice, suggesting a mechanism by which LKB1 enhances neuronal growth capacity. Systemic delivery of a modified AAV9 vector to upregulate LKB1 in neurons offers a potentially non-invasive therapeutic approach for treating CNS injuries and improving functional recovery.

Practical Implications

Therapeutic Target Identification

LKB1 is identified as a critical molecular target for enhancing the growth capacity of mature neurons, making it a key focus for developing treatments for CNS injuries.

Non-Invasive Treatment Potential

Systemic delivery of mAAV9-LKB1 offers a potential non-invasive gene therapy approach for treating CNS disorders, including spinal cord injury.

Improved Functional Recovery

Upregulation of LKB1 significantly improves locomotor function recovery in adult mammals with spinal cord injury, providing a tangible benefit for patients.

Study Limitations

1
The study did not detect GFP-LKB1 signals in the regenerative CST axons caudal to the lesion.
2
The molecular and cellular basis for the difference in grid walk errors between AAV2-LKB1 and mAAV9-LKB1 treatments remains unknown.
3
Further studies are required to clarify the detailed signaling pathway of LKB1 in mature neurons.

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