The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury

The Journal of Neuroscience, 2017 · DOI: 10.1523/JNEUROSCI.0931-17.2017 · Published: July 26, 2017

Spinal Cord Injury Pharmacology Neurology

Simple Explanation

The study investigates the role of S6K1, a downstream target of mTOR, in axon regeneration. It was found that inhibiting S6K1 in CNS neurons promotes neurite outgrowth in vitro. Treating mice with a selective S6K1 inhibitor stimulated corticospinal tract regeneration and locomotor recovery after spinal cord injury.

Study Duration

8 weeks

Participants

30 adult C57BL/6 female mice

Evidence Level

Not specified

Key Findings

1
Inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro.
2
Treatment with the S6K1 inhibitor PF-4708671 stimulated corticospinal tract regeneration across a dorsal spinal hemisection in mice.
3
Pharmacological targeting of S6K1 may constitute an attractive strategy for promoting axon regeneration following CNS injury.

Research Summary

The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold. Treating female mice in vivo with PF-4708671 stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6).

Practical Implications

Therapeutic Target

S6K1 represents a potential therapeutic target for promoting axon regeneration after CNS injury.

Clinical Translation

S6K1 inhibitors, already in clinical trials for other indications, could be repurposed for CNS injury treatment.

mTOR Pathway Modulation

Modulating the mTOR pathway through S6K1 inhibition offers a strategy to enhance axon regeneration without the risks associated with PTEN inactivation.

Study Limitations

1
Only female mice were used in the in vivo studies.
2
The study cannot rule out a role for S6K2.
3
It is not possible to directly compare experiments done in different laboratories

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