Society for Neuroscience Chicago Spinal Cord Injury: Restorative Strategies Trauma Poster Poster 226. Spinal Cord Injury: Restorative Strategies Location: Hall A Time: Sunday, October 18, 2015, 1:00 PM – 5:00 PM Program#/Poster#: 226.28/H38 Topic: C.10. Support: CIHR FRSQ NSERC-CREATE Neuroengineering training program
Authors: *A. KAPLAN1, A. KRONER1, S. LEONG1, C. MADWAR1, S. BANERJEE2, I. RAMBALDI1, N. BISSON2, J. ANTEL1, S. DAVID1, A. FOURNIER1; 1McGill Univ., Montreal, QC, Canada; 2Laval Univ., Quebec, QC, Canada
Disclosures: A. Kaplan: None. A. Kroner: None. S. Leong: None. C. Madwar: None. S. Banerjee: None. I. Rambaldi: None. N. Bisson: None. J. Antel: None. S. David: None. A. Fournier: None.
Spinal cord injury (SCI) results in the damage and disconnection of long axonal tracts. The inability of severed axons to regenerate is responsible for sustained paralysis and loss of sensation in SCI patients. An important strategy to approach this unmet need is to develop drugs that promote regenerative axon growth. We have identified 14-3-3 proteins, a family of phosphoserine/threonine-binding cytosolic adaptor proteins, as important mediators of axon regeneration. Overexpression of 14-3-3 isoforms enhances axon regeneration in an in vitro cortical neuron scratch assay. Moreover, we have identified a compound that stimulates axon regeneration through a putative mechanism of stabilization of 14-3-3 protein-protein interactions (PPIs).
Treatment of rat cortical neurons and human fetal neurons with the 14-3-3 stabilizer compound enhances neurite outgrowth in a dose-dependent manner, indicating a conservation of activity from rodent to man. The 14-3-3 stabilizer compound is known to bind to a pocket created by the interface between the 14-3-3 binding groove and certain client proteins, forming a tri-partite complex that enhances the stability of the PPI. PPI stabilization is a unique concept in drug design that, unlike PPI inhibition, does not necessitate competition with a natural ligand for target binding. Current efforts are focused on elucidating the mechanism-of-action of the 14-3-3 stabilizer compound and testing its efficacy in stimulating corticospinal tract regeneration after dorsal hemisection SCI in mice. Compounds that stabilize 14-3-3 PPIs may be valuable neuroregenerative agents for use in SCI and other conditions characterized by axonal damage.
Extrinsic and intrinsic regulation of axon regeneration at a crossroads
by Andrew Caplan: Full Text Article