Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System Following Neural Injury
Abstract
A longstanding concept in neuroscience has been that the mature mammalian brain is incapable of axon regeneration. However, we have shown that it is possible to achieve long range axon growth by re-activation of intrinsic genetic programs that are active during development to mediate axon growth. We have found that activation of Akt/mTor signaling by AAV-mediated transduction with constitutively active forms of either the kinase Akt or the GTPase Rheb in a model of retrograde axonal degeneration induces axon growth by dopamine neurons. However, these molecules cannot be directly used in human therapeutics because they are oncogenes. The goal of this proposal is to develop a strategy to circumvent this problem. We have hypothesized that mediators downstream of mTor may diverge in their effects, making it possible to achieve axon growth without oncogenic risk. In Year 01 we have assessed the ability of the mTor target p70S6K to induce new axon growth. Transduction of dopamine neurons of the substantia nigra by AAV with a constitutively active form, p70S6K(delC/T389E), at three weeks after axonal destruction with the neurotoxin 6OHDA, induces new axon growth that reaches the target striatum. This growth was demonstrated by three techniques: immunostaining for tyrosine hydroxylase-positive axons in the medial forebrain bundle (MFB); quantification by confocal optical dissection of either GFP-positive axons in the MFB in transgenic TH-GFP mice, or of Tomato-positive axons following transduction with anterograde tracer Tomato-Tau.. We also determined that axons establish functional contact, demonstrated by reversal of a toxin-induced behavioral deficit. We conclude that p70S6K(delC/T389E) is an effective mediator of new axon growth.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2013
- Accession Number
- ADA602707
Entities
People
- Robert E Burke
Organizations
- Columbia University