Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration

• Published in: Neuron (Cambridge, Mass.) Vol. 93; no. 5; pp. 1082 - 1093.e5
• Main Authors: Kaplan, Andrew, Morquette, Barbara, Kroner, Antje, Leong, SooYuen, Madwar, Carolin, Sanz, Ricardo, Banerjee, Sara L., Antel, Jack, Bisson, Nicolas, David, Samuel, Fournier, Alyson E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2017; Elsevier Limited
• Subjects: 14-3-3; 14-3-3 protein; 14-3-3 Proteins - metabolism; Adaptor proteins; Animals; Animals, Newborn; Apoptosis; axon regeneration; Axonogenesis; Axons - metabolism; Cells, Cultured; Central nervous system; CNS injury; fusicoccin; GCN1; GCN2; Glycosides - metabolism; Mice; Molecular biology; Nerve Regeneration - physiology; Nervous system; Neurons; optic nerve; Phosphorylation; PPI stabilizer; Protein interaction; Proteins; Rats, Sprague-Dawley; Regeneration; Signal Transduction - physiology; spinal cord injury; stress response; 14-3-3; spinal cord injury; GCN2; stress response; CNS injury; axon regeneration; optic nerve; PPI stabilizer; GCN1; fusicoccin
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.02.018

Damaged central nervous system (CNS) neurons have a poor ability to spontaneously regenerate, causing persistent functional deficits after injury. Therapies that stimulate axon growth are needed to repair CNS damage. 14-3-3 adaptors are hub proteins that are attractive targets to manipulate cell signaling. We identify a positive role for 14-3-3s in axon growth and uncover a developmental regulation of the phosphorylation and function of 14-3-3s. We show that fusicoccin-A (FC-A), a small-molecule stabilizer of 14-3-3 protein-protein interactions, stimulates axon growth in vitro and regeneration in vivo. We show that FC-A stabilizes a complex between 14-3-3 and the stress response regulator GCN1, inducing GCN1 turnover and neurite outgrowth. These findings show that 14-3-3 adaptor protein complexes are druggable targets and identify a new class of small molecules that may be further optimized for the repair of CNS damage. •14-3-3 adaptor proteins facilitate axon growth•Stabilization of 14-3-3 complexes with Fusicoccin-A stimulates axon regeneration•Fusicoccin-A targets a complex between 14-3-3 and the stress response regulator GCN1•GCN1 acts as an intrinsic brake on neurite outgrowth Kaplan et al. describe a novel pharmacological strategy with a unique mechanism of action to enhance axon regeneration in the injured CNS. Fusicoccin-A stabilizes 14-3-3 protein complexes and stimulates nerve regeneration, in part through modulation of the stress response regulator GCN1.