Role of Stress Granule Protein Aggregation in Axon Regeneration

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Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. Nerve injury significantly impacts long-term quality of life, and most injured individuals seek continued treatments for associated disabilities and pain. The most common explanation for poor functional outcomes is the slow and inefficient process of axon regeneration. Proteins synthesized locally in axons contribute to peripheral nerve regeneration by providing retrograde signals for injury responses and supporting axon regrowth locally. We have shown that mRNAs are stored in PNS axons in RNA-protein aggregates that contain the stress granule protein G3BP1. G3BP1 protein can drive stress granule aggregation, and G3BP1 phosphorylation blocks stress granule assembly. G3BP1 binds to mRNAs in axons and attenuates their translation. We have discovered exogenous agents and endogenous signals that trigger disassembly of axonal G3BP1 aggregates. The exogenous agents specifically increase axonal protein synthesis and accelerate axon growth rates in vitro and in vivo. However, translational regulation of axonal mRNAs has been demonstrated in models of neuropathic pain, and nerve injury patients frequently seek additional treatment after peripheral nerve injury for the development of neuropathic pain. Whether acute disassembly of G3BP1 RNAs within nociceptive neurons will lead to or exacerbate neuropathic pain is unknown and is a key step toward translatability of this type of therapy. This ‘Research Supplement to Promote Diversity in Health-Related Research’ is designed to bring translational research experience to a post- baccalaureate fellow with mentoring from a team of one junior and two senior investigators. This will prepare the fellow for graduate school and strengthen her applications.