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.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015696:Gene Products, tat / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D015696:Gene Products, tat; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein