Manipulation of the local translation of Rho GTPases in axons to support axon regeneration
Funded in: 2018, 2019, 2020
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Problem: Impaired axon regeneration after CNS injury
Target: Intrinsic neuron growth capacity to encourage axon regeneration
Goal: Change the balance in local translation of Rho GTPases to increase axon growth and regeneration after spinal cord injury
Regeneration of severed axons is a major challenge for recovery of function after spinal cord injury. These connections between neurons in the brain and spinal cord that are lost with spinal cord injury have a low intrinsic growth capacity, so those connections are often permanently lost. The environment of the injured spinal cord also actively blocks regeneration of axons. Proteins made by glial cells in the injured spinal cord establish this non-permissive extracellular environment that prevents regeneration in the spinal cord.
The balance of intrinsic growth properties and signals from the extracellular environment is a critical determinant for whether an injured axon can grow, with signals from the environment regulating intracellular axon growth pathways. Activities of small GTPase proteins in the ends of axons, the Rho GTPase family, are critical determinants of axon growth. Two members of this family, RhoA and Cdc42, have opposite effects with RhoA blocking growth and Cdc42 activating growth of axons. Growth inhibitory proteins from the injured spinal cord activate RhoA signaling in axons, and blocking RhoA activation encourages axon growth. Previous work has shown that RhoA protein can be synthesized locally in axons, so localized protein synthesis contributes to axon growth failure. We have discovered that Cdc42 is also locally synthesized in axons, and locally synthesized Cdc42 increases axon growth. The Cdc42 gene encodes two different proteins that have distinct lipid modifications, and only one of those proteins is needed for axon growth promotion.
We will test the possibility that the balance between synthesis of Cdc42 and RhoA proteins in axons determines how the axon responds to its extracellular environment. Specifically, can we promote axon regeneration by preventing synthesis of RhoA protein and promoting synthesis of Cdc42 protein in axons? We will first determine the mechanisms for translation of axonal Cdc42 and RhoA mRNAs by growth-promoting signals and growth-inhibiting proteins. We will next test the possibility that shifting the balance to Cdc42 increases synthesis of other growth supporting proteins in axons. Finally, we will determine if we can maximize synthesis of Cdc42 while minimizing synthesis of RhoA to encourage axon growth in growth-inhibiting environments. Overall, this work will tell us if axonal Cdc42 can be targeted to increase regeneration after spinal cord injury.