title: Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration.
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.
authors.affiliation: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kaplan
authors.affiliation: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Morquette
authors.affiliation: 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.
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.affiliation: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: SooYuen
authors.initials: S
authors.lastname: Leong
authors.affiliation: Department of Chemistry, McGill University, Montréal, QC H3A 0B8, Canada.
authors.forename: Carolin
authors.initials: C
authors.lastname: Madwar
authors.affiliation: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sanz
authors.affiliation: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec City, QC G1V 0A6, Canada.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Banerjee
authors.affiliation: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, and Centre de Recherche sur le Cancer, Université Laval, Québec City, QC G1V 0A6, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bisson
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montréal, QC H3G 1A4, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: David
authors.affiliation: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada. Electronic address: alyson.fournier@mcgill.ca.
authors.forename: Alyson E
authors.initials: AE
authors.lastname: Fournier
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D006027:Glycosides / Q000378:metabolism*; D051379:Mice; D009416:Nerve Regeneration / Q000502:physiology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; D006027:Glycosides; C007808:fusicoccin
keywords: 14-3-3; CNS injury; GCN1; GCN2; PPI stabilizer; axon regeneration; fusicoccin; optic nerve; spinal cord injury; stress response