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

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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.

Keywords: CSPG; Gene therapy; Lentivirus; Myelin; Semaphorin; Spinal cord injury

Document Type: Review Article

DOI: http://dx.doi.org/10.3727/000000007783464740

Affiliations: Department of Neurosurgery, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA

Publication date: March 1, 2007

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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