Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration. Neuron 2017 Mar 08;93(5):1082-1093.e5
Date
03/11/2017Pubmed ID
28279353DOI
10.1016/j.neuron.2017.02.018Scopus ID
2-s2.0-85014753970 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
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 AEAuthor
Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
14-3-3 ProteinsAnimals
Animals, Newborn
Axons
Cells, Cultured
Glycosides
Mice
Nerve Regeneration
Rats, Sprague-Dawley
Signal Transduction
