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Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration. Neuron 2017 Mar 08;93(5):1082-1093.e5

Date

03/11/2017

Pubmed ID

28279353

DOI

10.1016/j.neuron.2017.02.018

Scopus ID

2-s2.0-85014753970   45 Citations

Abstract

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.

Author List

Kaplan A, Morquette B, Kroner A, Leong S, Madwar C, Sanz R, Banerjee SL, Antel J, Bisson N, David S, Fournier AE

Author

Antje Kroner-Milsch MD, PhD Assistant Professor in the Neurosurgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

14-3-3 Proteins
Animals
Animals, Newborn
Axons
Cells, Cultured
Glycosides
Mice
Nerve Regeneration
Rats, Sprague-Dawley
Signal Transduction