# Role of Stress Granule Protein Aggregation in Axon Regeneration

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $575,416

## Abstract

Peripheral nerves spontaneously regenerate but the axon growth rate is abysmally slow, such that 
complete functional reinnervation of targets is rarely achieved in humans. Axon regeneration in 
the central nervous system is even worse, such that individuals with spinal cord injury (SCI) 
almost invariably have permanent lose of sensory and motor functions below the level of the lesion. 
 There is a pressing need to accelerate axon regeneration in the peripheral nervous system and 
increase axon regeneration in the central nervous system. Our research program focuses on axon 
intrinsic mechanisms of regeneration. Intra-axonally synthesized proteins support axon growth in 
developing neurons. We have shown that PNS neurons retain the capacity to synthesize proteins in 
their axons and these proteins support growth of injured axons. Axons of cultured neurons contain 
thousands of mRNAs – and several lines of evidence point to complex populations of mRNAs in CNS 
axons in vivo and spinal cord axons contain mRNAs and translational machinery when encouraged to 
regenerate with permissive substrates. Despite
remarkable advances since the early 2000’s, the molecular mechanisms that determine when and where 
a specific mRNA is translated in axons remain largely unknown. This level of regulation is 
critical for regulating axon growth capacity. 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. Unlike the 
classically defined stress granule, axonal G3PB1 protein shows aggregation in uninjured/functioning 
PNS axons. These axonal G3BP1 aggregates rapidly increase after axotomy, but decrease to below 
basal levels shortly thereafter with a corresponding increase in phosphorylated G3BP1. 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. These observations have led us to hypothesize that physiological aggregation of stress 
granule proteins in axons attenuates axon growth in the injured PNS and CNS by blocking translation 
of an axonal mRNA cohort. We will test this hypothesis with the following specific aims:
Aim 1 – Promotion of axon growth by inhibition of G3BP1 function.
Aim 2 – Endogenous mechanisms for axonal G3BP1 aggregate disassembly.
Aim 3 – Mechanisms driving axon growth upon disassembly of axonal G3BP1 aggregates.
Functional roles for axonal translation have now come to light and we have solid in vivo evidence 
that this mechanism can be targeted to accelerate axon growth after acute peripheral nerve injury. 
Completion of the proposed research will bring new insight into mechanisms for temporal regulation 
of axonal mR...

## Key facts

- **NIH application ID:** 10030563
- **Project number:** 1R01NS117821-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** JEFFERY L TWISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $575,416
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030563

## Citation

> US National Institutes of Health, RePORTER application 10030563, Role of Stress Granule Protein Aggregation in Axon Regeneration (1R01NS117821-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10030563. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*