S6 Kinase Puts a Surprising Brake on Axon Regeneration
Material below summarizes the article The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury, published on June 16, 2017, in JNeurosci and authored by Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, Vance P. Lemmon, and John L. Bixby.
Neurons of the adult central nervous system (CNS) are often incapable of regenerating their long processes (axons).
These axons connect distant areas within the brain and spinal cord, allowing communication within the CNS and from the CNS to the rest of the body. Without regeneration, injuries that sever these axons can permanently damage sensation, movement, and other critical functions.
In this study, we used a novel computational approach to identify a set of signaling proteins called kinases that work together within neurons to “apply the brakes” on axon growth. Surprisingly, one of the kinases we identified as an inhibitory brake, S6 kinase (S6K), was previously thought to serve the exact opposite function as an accelerator of axon growth.
To test the idea that S6K provides a brake on axon growth, we treated neurons in tissue culture with a selective inhibitor of S6K, called PF-4708671 (PF for short). PF blocked S6K enzymatic activity inside the neurons as expected. Interestingly, the block in S6K activity was accompanied by substantial increases in axon growth from treated neurons, indicating that S6K acts as a brake.
We then explored a different method for switching off S6K activity, using small interfering RNAs (siRNAs) directed at the S6K gene. These siRNAs turn down the production of S6K protein inside cells. Reducing production of neuronal S6K protein, like the block of S6K activity, led to a clear increase in axon growth.
How does reducing S6K activity increase axon growth?
To answer this, we turned to another important kinase called mTOR that lies at the heart of a key pathway regulating axon growth. Activation of mTOR strongly promotes growth —that is, mTOR is a growth accelerator. We know that mTOR activates several other kinases, one of which is S6K. This observation, in fact, had led some scientists to assume that S6K would also be an axon growth accelerator.
However, we found that S6K activity is not required for mTOR’s ability to promote axon growth. Instead, we found that in neurons, activation of S6K can switch off mTOR activity, providing a negative feedback loop. When we inhibited S6K with PF, we observed a big surge in mTOR activity, which appeared to be responsible for the ability of PF to promote axon growth.
S6K, therefore, appears to repress axon growth by inhibiting mTOR activity, and inhibition of S6K removes this intracellular brake on axon growth.
So, does S6K also act to slow regrowth of injured axons after trauma to the mammalian CNS?
To investigate this question, we injected PF into the brains of mice whose spinal cords had been severed by injury. The injury destroys the connections between the brain neurons and elements of the nervous system that control fine movement and sensation.
Remarkably, injection of PF into the brain allowed regeneration of these cut axons. Moreover, PF substantially improved functional recovery in tests of controlled movement.
The results suggest that S6K may be a useful target for developing drugs that treat CNS injury. This is exciting because drugs that target S6K are already being developed, and may one day be repurposed for helping patients with CNS injuries.
The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury. Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, V.P. Lemmon, and J.L. Bixby. JNeurosci Jun 2017, DOI: https://doi.org/10.1523/JNEUROSCI.0931-17.2017