Targeting 14-3-3 adaptor protein-protein interactions to stimulate central nervous system repair

Neural Regeneration Research, 2017 · DOI: 10.4103/1673-5374.211176 · Published: July 1, 2017

Pharmacology Regenerative Medicine Neurology

Simple Explanation

Central nervous system (CNS) axons have a poor capacity for re-growth after injury, leading to permanent disruption of neuronal communication. Therapies are needed to induce regrowth of damaged axons or sprouting from intact axons to restore functional connectivity. This review discusses a new pharmacological strategy for enhancing axon growth and regeneration by targeting a family of adaptor proteins called 14-3-3s with a small molecule called fusicoccin-A. Fusicoccin-A stabilizes 14-3-3 interactions with client proteins, promoting axon growth and regeneration, and could serve as a starting point for developing drugs to induce CNS repair.

Study Duration

Not specified

Participants

Rodent and human neurons

Evidence Level

In vitro and in vivo studies

Key Findings

1
Fusicoccin-A (FC-A) stimulates neurite outgrowth from rodent cortical neurons and primary human fetal neurons by stabilizing 14-3-3 protein-protein interactions (PPIs).
2
In an optic nerve crush model, local intravitreal injections of FC-A stimulated axon regeneration up to 0.5-1 mm past the lesion without improving cell survival.
3
FC-A reduces axonal die-back in the spinal cord using the dorsal hemisection model, suggesting its potential for axonal repair.

Research Summary

The review focuses on the potential of targeting 14-3-3 adaptor proteins with small molecule drugs to enhance axon outgrowth and regeneration in the central nervous system (CNS). Fusicoccin-A (FC-A), a fungus-derived small molecule, stabilizes 14-3-3 interactions with client proteins, promoting axon growth and regeneration, making it a potential starting point for drug development. Further research into the mechanisms underlying FC-A's effect on axon growth and chemical modification of FC-A could lead to client-specific drugs for treating CNS injury.

Practical Implications

Drug Development

Fusicoccin-A and its derivatives can be further explored for the development of new drugs targeting 14-3-3 protein-protein interactions to promote axon regeneration.

Therapeutic Target

14-3-3 proteins and their client complexes, such as 14-3-3:GCN1, can be targeted to stimulate repair in various CNS injuries and diseases, including stroke and neurodegeneration.

Combination Therapies

Combining FC-A treatment with pharmacological or genetic blockade of apoptosis could greatly enhance its effects on regeneration in models such as optic nerve crush.

Study Limitations

1
The mechanisms underlying the effects of FC-A on axon growth remain unclear.
2
It is currently unknown whether FC-A-related compounds can cross the blood-brain barrier.
3
The effect of FC-A on secondary events after injury, including astrocytic scar formation, inflammation, and re-myelination, remains to be examined.

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