Kavli Affiliate: Mark H. Tuszynski;
| Authors: Pabitra K Sahoo, Nick Hanovice, Patricia Ward, Manasi A Agrawal, Terika P Smith, HaoMin SiMa, Jennifer N Dulin, Lauren S Vaughn, Mark Tuszynski, Kristy Welshhans, Larry Benowitz, Arthur English, John D Houle and Jeffery L Twiss
| Summary:
Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in C. elegans, increases axon regeneration in injured neurons that show spontaneous regeneration. Inhibition of G3BP1 by expression of its acidic or B-domain accelerates axon regeneration after nerve injury bringing a potential therapeutic intervention to promote neural repair in the peripheral nervous system. Here, we asked if G3BP1 inhibition is a viable strategy to promote regeneration in the injured mammalian central nervous system where axons do not regenerate spontaneously. G3BP1 B-domain expression was found to promote axon regeneration in both the mammalian spinal cord and optic nerve. Moreover, a cell permeable peptide to a subregion of G3BP1 B-domain (rodent G3BP1 amino acids 190-208) accelerated axon regeneration after peripheral nerve injury and promoted the regrowth of reticulospinal axons into the distal transected spinal cord through a bridging peripheral nerve graft. The rodent and human G3BP1 peptides promoted axon growth from rodent and human neurons cultured on permissive substrates, and this function required alternating Glu/Asp-Pro repeats that impart a unique predicted tertiary structure. These studies point to G3BP1 granules as a critical impediment to CNS axon regeneration and indicate that G3BP1 granule disassembly represents a novel therapeutic strategy for promoting neural repair after CNS injury.