Hyperactive delta isoform of PI3 kinase enables long-distance regeneration of adult rat corticospinal tract

Molecular Therapy, 2025 · DOI: https://doi.org/10.1016/j.ymthe.2024.12.040 · Published: February 1, 2025

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This study addresses the challenge of limited axon regeneration in the adult mammalian spinal cord following injury. It focuses on enhancing the PI3K/Akt pathway, crucial for promoting growth, which diminishes as neurons mature. The research introduces a hyperactive PI3K isoform, PI3Kd, to boost PIP3 levels in mature cortical neurons. PIP3 influences cell motility, protein translation, transport, and various other functions through signaling pathways. Results indicate that PI3Kd upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post spinal cord injury. Treated rats showed improvements in paw reaching, grip strength, and ladder-rung walking.

Study Duration

16 weeks

Participants

Adult Wistar and Lister Hooded rats

Evidence Level

Not specified

Key Findings

1
PI3Kd treatment increased sprouting of axons across the midline above the C4 lesion and reduced the number and distance of retraction bulbs from the lesion border.
2
Overexpressing PI3Kd leads to the growth and sprouting of many axons over long distances below the C4 lesion.
3
Overexpressing PI3Kd improved behavioral outcomes and was motor function specific; electrophysiology recordings confirmed functional improvements.

Research Summary

This study tested the ability of PI3Kd to enable axon regeneration of adult CST axons in rat spinal cord after injury and to restore sensorimotor function and physiological connectivity. AAV1-mediated delivery of PI3Kd resulted in expression in many output neurons in the sensorimotor cortex, protecting neurons from atrophy but without causing neural soma hypertrophy. Overall, the study shows that PI3Kd expression stimulates extensive CST regeneration, electrophysiological connectivity, and functional recovery.

Practical Implications

Combination Therapies

PI3Kd treatment could be combined with other stimulators of regeneration and with rehabilitation, such as chondroitinase ABC.

Integrin Enhancement

Combining PI3Kd with integrin a9 and kindlin-1 could further enhance axon regeneration, especially for sensory axons.

S6 Phosphorylation Inhibition

A combination of PI3Kd with an inhibitor of S6 phosphorylation is another potentially successful combination to promote CST regeneration.

Study Limitations

1
It is not possible to determine definitively in our model how much of this PI3Kd-driven recovery is due to long-distance regeneration, sprouting above the lesion, and sprouting from the intact vCST.
2
The large number of regenerated axons growing in the ipsilateral and contralateral cord and their ability to form synapses suggests that they participated significantly, but sprouting above the lesion was extensive.
3
A contribution may also come from the extrapyramidal tracts—rubrospinal and reticulospinal—although these pathways would not have been directly affected by our PI3Kd treatment, which was only delivered to cortical neurons.

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