2. Academic Validation
  3. Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration

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

  • Neuron. 2017 Mar 8;93(5):1082-1093.e5. doi: 10.1016/j.neuron.2017.02.018.
Andrew Kaplan 1,  Barbara Morquette 1,  Antje Kroner 2,  SooYuen Leong 1,  Carolin Madwar 3,  Ricardo Sanz 1,  Sara L Banerjee 4,  Jack Antel 1,  Nicolas Bisson 4,  Samuel David 5,  Alyson E Fournier 6
Affiliations

Affiliations

  • 1 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • 2 Department of Neurosurgery, Medical College of Wisconsin, VA Medical Center, Milwaukee, WI 53295, USA; Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montréal, QC H3G 1A4, Canada.
  • 3 Department of Chemistry, McGill University, Montréal, QC H3A 0B8, Canada.
  • 4 Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec City, QC G1V 0A6, Canada.
  • 5 Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montréal, QC H3G 1A4, Canada.
  • 6 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada. Electronic address: alyson.fournier@mcgill.ca.
PMID: 28279353 DOI: 10.1016/j.neuron.2017.02.018
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.

Keywords

14-3-3; CNS injury; GCN1; GCN2; PPI stabilizer; axon regeneration; fusicoccin; optic nerve; spinal cord injury; stress response.

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