The RSK2-RPS6 axis promotes axonal regeneration in the peripheral and central nervous systems

PLoS Biology, 2023 · DOI: https://doi.org/10.1371/journal.pbio.3002044 · Published: April 17, 2023

Regenerative Medicine Neurology Genetics

Simple Explanation

Mature neurons in the central nervous system (CNS) typically don't regenerate after injury, leading to permanent disabilities. This study identifies a pathway involving RPS6 phosphorylation, crucial for nerve regeneration in both the peripheral (PNS) and central nervous systems. The researchers found that RPS6 phosphorylation, specifically at Ser235-236, is essential for both PNS regeneration and the 'preconditioning effect,' where a prior injury primes neurons for regeneration. This phosphorylation is controlled by the RSK2 kinase. The study demonstrates that RSK2 promotes CNS regeneration in the spinal cord, enhances synaptic plasticity, and restores target innervation, ultimately leading to functional recovery after injury. This highlights the critical role of RSK2-mediated RPS6 phosphorylation in CNS regeneration.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
RPS6 phosphorylation on Ser235-236 is essential for PNS and CNS regeneration in mice.
2
RSK2 controls the preconditioning effect and that the RSK2-RPS6 axis is key for this process, as well as for PNS regeneration.
3
RSK2 promotes CNS regeneration in the dorsal column, spinal cord synaptic plasticity, and target innervation leading to functional recovery.

Research Summary

This study investigates the role of RPS6 phosphorylation in axon regeneration in the peripheral and central nervous systems. It identifies that phosphorylation of RPS6, particularly at Ser235-236, is crucial for both PNS regeneration and the preconditioning effect. The research demonstrates that the p90S6 kinase RSK2 controls RPS6 phosphorylation and is essential for the preconditioning effect and PNS regeneration. The study further reveals that RSK2 promotes CNS regeneration, synaptic plasticity, and functional recovery, establishing the RSK2/RPS6 axis as a critical pathway in nervous system regeneration.

Practical Implications

Therapeutic Target

The RSK2-RPS6 pathway may represent a novel therapeutic target for promoting axon regeneration and functional recovery after CNS injuries.

Independent Pathway

Understanding that RSK2 controls RPS6 phosphorylation independently of mTOR provides new avenues for therapeutic intervention.

Combination Therapies

Combining RSK2 activation with other regeneration-promoting strategies could lead to synergistic effects and improved outcomes.

Study Limitations

1
The study focuses primarily on mice; further research is needed to determine the translatability of these findings to humans.
2
The precise downstream mechanisms by which RPS6 phosphorylation promotes axon regeneration remain to be fully elucidated.
3
The role of other RSK family members and their potential interactions with RSK2 in axon regeneration warrant further investigation.

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