Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia

Curr Biol, 2021 · DOI: 10.1016/j.cub.2021.04.079 · Published: July 26, 2021

Simple Explanation

Mitochondria provide energy crucial for neurons to survive and regenerate, but brain injuries and ischemia disrupt this energy supply, leading to neuron damage. This study reveals a mechanism where the AKT-PAK5 signaling pathway helps restore energy in injured axons. The PAK5 protein, normally less active in mature neurons, gets reactivated after injury or ischemia. This activation helps move and replace damaged mitochondria in axons, ensuring a continuous energy supply for repair. The AKT growth signal further enhances PAK5 activity, accelerating the repair process and protecting neurons. Reprogramming this pathway could potentially be a therapeutic strategy for brain injuries and ischemia.

Study Duration

Not specified

Participants

Adult mice, embryonic mice, cell lines

Evidence Level

Not specified

Key Findings

1
Axonal PAK5 synthesis and signaling are activated in response to ischemia and injury, promoting neuron survival.
2
PAK5 localizes on axonal mitochondria surfaces and its activation leads to remobilization of axonal mitochondria in mature neurons.
3
PAK5-mediated phosphorylation of syntaphilin (SNPH) at specific sites turns off its anchoring capacity, allowing mitochondria to move freely.

Research Summary

The study elucidates an injury-induced AKT-PAK5-SNPH signaling axis that maintains axonal energy supply after acute injury-ischemia in mature neurons and adult brains. Reprogramming PAK5 signaling removes SNPH-anchored damaged mitochondria and replenishes with healthy ones in injured axons, thus reversing energy crisis. This intrinsic energy repair signaling is efficient in protecting neuron survival and facilitating regeneration after brain injury and ischemia.

Practical Implications

Therapeutic Potential

Reprogramming the AKT-PAK5-SNPH axis represents a potential therapeutic target for effective recovery from acute mitochondrial damage during brain injury and ischemic stroke.

Targeted Drug Development

Developing drugs that enhance PAK5 activity or disrupt SNPH anchoring could improve outcomes after brain injuries.

Understanding Regeneration

Further research into this pathway could provide insights into promoting CNS regeneration, which is typically limited.

Study Limitations

1
The study primarily focuses on in vitro and in vivo models, and further clinical trials are needed to validate the findings in humans.
2
The precise mechanisms regulating the spatiotemporal activation of PAK5 after injury require further investigation.
3
The long-term effects of reprogramming the AKT-PAK5 axis on neuronal function and potential side effects need to be thoroughly evaluated.

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