Stimulating the intrinsic axonal growth potential (epigenetics and transcriptional regulation)
Molecular mechanisms shown to be involved in neuroregeneration of the peripheral nervous system (PNS) have been found to also initiate central nervous system (CNS) regeneration. For example, following a conditioning lesion of the PNS branch (sciatic nerve lesion) of the dorsal root ganglion (DRG) prior to a CNS spinal cord injury (SCI), de novo transcription has been shown to lead to CNS axonal regeneration. This led to the discovery of regeneration associated genes (RAGs) found to be increased in the DRG after a conditioning lesion but not a CNS dorsal column lesion. Overexpression of one or two of the RAGs did not lead to recapitulation of the conditioning effect, therefore interest turned to the regulation of multiple RAGs, hence transcriptional and epigenetic regulation. We have previously shown that when the histone acetylatranferase p300/CBP associated factor (PCAF) is overexpressed virally it is capable of recapitulating the conditioning effect and when deleted it abrogates the conditioning effect. We are currently evaluating various transcriptional factors that work in concert with PCAF to produce the upregulation of key RAGs and which upstream pathways may be involved in their activation. From this knowledge we will develop either pharmaceutical or gene therapy interventions.
Collaboration with Dr. Simone Di Giovanni (Imperial College-London, U.K.) and Dr. Anne-Laurence Boutillier (University of Strasbourg, France)
Viral overexpression of PCAF in both permissive (Laminin) and non-permissive (Myelin) growth environments in vitro increases the neurite length of adult dorsal root ganglion neurons (A-B). Correspondingly, viral overexpression of PCAF in vivo induces axonal growth into and through the lesion site (C). Quantification shows the percent of sensory fibers that traverse the lesion and grow up to a millimeter past the lesion site after PCAF viral neuronal infection (D).
Lindner R., Puttagunta R., Nguyen T. and Di Giovanni S. (2014). DNA methylation temporal profiling following peripheral versus central nervous system axotomy. Scientific Data 1. Article number 140038. Link to article.
Puttagunta R.$, Tedeschi A.$, Soria M.G., Hervera A., Lindner R., Rathore K.I., Gaub P., Joshi Y., Nguyen T., Schmandke A., Laskowski C.J., Boutillier A.-L., Bradke F. and Di Giovanni S. (2014). PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nature Communications 5: 3527. Link to article.
Lindner R., Puttagunta R. and Di Giovanni S. (2013). Epigenetic regulation of axon outgrowth and regeneration in CNS injury: the first steps forward. Neurotherapeutics. 10(4): 771-81. . Link to article.