Inhibition of neuronal apoptosis in vitro and in vivo using TAT-mediated protein transduction.

The HIV TAT protein contains an 11-amino-acid protein transduction domain which acts as a "Trojan peptide": Linked to other macromolecules, it carries them across cellular membranes. Here, we demonstrate for the first time that fusion of the TAT protein transduction domain to an antiapoptotic protein represents a feasible technique to rescue neurons from apoptotic degeneration in vitro and in vivo. When fused to the antiapoptotic protein Bcl-X(L), it mediated uptake of the fusion protein into neurons. Once inside the cells, TAT-Bcl-X(L) was stable for many days and maintained its antiapoptotic function. It completely blocked low-potassium-induced apoptosis of cerebellar granule cells in vitro. In vivo, 24% of mouse retinal ganglion cells were prevented from undergoing retrograde neuronal apoptosis caused by optic nerve lesion when TAT-Bcl-X(L) was intraocularly injected. The application of TAT fusion proteins may in the future greatly facilitate neuroprotective therapy strategies for neurological disorders.