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

Mol Cell Neurosci. 2002 Sep;21(1):29-37. doi: 10.1006/mcne.2002.1165.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cells, Cultured
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Disease Models, Animal
  • Gene Products, tat / genetics
  • Gene Products, tat / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / prevention & control
  • Neurons / drug effects
  • Neurons / metabolism
  • Protein Structure, Tertiary / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology*
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology
  • Transduction, Genetic / methods*
  • bcl-X Protein

Substances

  • Bcl2l1 protein, mouse
  • Bcl2l1 protein, rat
  • Gene Products, tat
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-X Protein