The Pivotal Role of RhoA GTPase in the Molecular Signaling of Axon Growth Inhibition after CNS Injury and Targeted Therapeutic Strategies

Abstract

The dogma that the adult central nervous system (CNS) is nonpermissive to axonal regeneration is beginning to fall in the face of increased understanding of the molecular and cellular biology of axon outgrowth. It is now appreciated that axon growth is regulated by a combination of extracellular factors related to the milieu of the developing or adult CNS and the presence of injury, and intracellular factors related to the "growth state" of the developing or regenerating neuron. Several critical points of convergence within the developing or regenerating neuron for mediating intracellular cell signaling effects on the growth cone cytoskeleton have been identified, and their modulation has produced marked increases in axon outgrowth within the "nonpermissive" milieu of the adult injured CNS. One such critical convergence point is the small GTPase RhoA, which integrates signaling events produced by both myelin-associated inhibitors (e.g., NogoA) and astroglial-derived inhibitors (chondroitin sulfate proteoglycans) and regulates the activity of downstream effectors that modulate cytoskeletal dynamics within the growth cone mediating axon outgrowth or retraction. Inhibition of RhoA has been associated with increased outgrowth on nonpermissive substrates in vitro and increased axon regeneration in vivo. We are developing lentiviral vectors that modulate RhoA activity, allowing more long-term expression than is possible with current approaches. These vectors may be useful in regenerative strategies for spinal cord injury, brain injury, and neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease.

Control of Axonal Growth and Regeneration of Sensory Neurons by the p110δ PI 3-Kinase

“…These observation is in line with the idea that p110δ can suppress cellular RhoA but not Rac activity under basal conditions [23]. RhoA is a critical mediator of the inhibitory effect of several axon guidance molecules and myelin associated inhibitors [32], [33]. Inhibition of RhoA, or its downstream effector ROCK, is able to restore outgrowth in an inhibitory environment provided by myelin or myelin associated inhibitors [32], [33].…”

“…RhoA is a critical mediator of the inhibitory effect of several axon guidance molecules and myelin associated inhibitors [32], [33]. Inhibition of RhoA, or its downstream effector ROCK, is able to restore outgrowth in an inhibitory environment provided by myelin or myelin associated inhibitors [32], [33]. In order to test the significance of increased RhoA function for p110δ signaling during axonal elongation, we inhibited ROCK using the small molecule inhibitor Y27632 [34]–[36].…”

Peripheral administration of bovine GH regulates the expression of cerebrocortical beta-globin, GABAB receptor 1, and the Lissencephaly-1 protein (LIS-1) in adult hypophysectomized rats

“…relation to neuroprotection/regeneration or trophic/memory), and references. Details of abbreviated references in the table:[25,27,29,33,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. For some transcripts the description of function is partially retrieved from the Medical subjects heading (MESH) at http://www.ncbi.nlm.nih.gov/pubmed.…”

Scar-modulating treatments for central nervous system injury

“…RhoA, a small GTPase, leads to cytoskeleton collapse and inhibits axon regeneration though ROCK activation [99] .…”