Preprint
Disruption of Core Stress Granule Protein Aggregates Promotes CNS Axon Regeneration
bioRxiv : the preprint server for biology
08 Jun 2024
PMID: 38895344
Abstract
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's 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.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's 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.
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Details
- Title
- Disruption of Core Stress Granule Protein Aggregates Promotes CNS Axon Regeneration
- Creators
- Pabitra K Sahoo - University of South CarolinaNick Hanovice - Dimagi (United States)Patricia Ward - AID AtlantaManasi Agrawal - University of South CarolinaTerika P Smith - University of South CarolinaHaoMin SiMa - AID AtlantaJennifer N Dulin - Texas A&M UniversityLauren S Vaughn - University of South CarolinaMark Tuszynski - University of California San DiegoKristy Welshhans - University of South CarolinaLarry Benowitz - Dimagi (United States)Arthur English - AID AtlantaJohn D Houle - Drexel UniversityJeffery L Twiss - University of South Carolina
- Publication Details
- bioRxiv : the preprint server for biology
- Publisher
- American Physical Society (APS)
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Other Identifier
- 991021889614004721