Inhibition of axotomy-induced neuronal apoptosis by extracellular delivery of a Bcl-XL fusion protein.
Bcl-2 and Bcl-XL prevent neuronal apoptosis during development, neurodegenerative disease, and trauma. To test a new anti-apoptosis strategy for neuroprotection, we engineered nontoxic components of anthrax toxin into a Bcl-XL delivery system. Delivery of Bcl-XL by this system prevented apoptosis of cultured rat cerebellar granule cells and macrophages, and the prevention depended on both the Bcl-XL and the anthrax toxin receptor binding/translocation moieties. Furthermore, neuronal death in vivo in a retinal ganglion cell model of axotomy-induced apoptosis was inhibited by administration of this fusion protein. Thus, Bcl-XL protein can be delivered into cells from the medium or interstitial space, offering a new way to block apoptosis upstream of many caspases and the mitochondria dysfunction phase of apoptosis.
Liu
X H
XH
Biochemistry Section, Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA.
Collier
R J
RJ
Youle
R J
RJ
D000818:Animals; D000942:Antigens, Bacterial; D017209:Apoptosis / Q000187:drug effects*; D019771:Axotomy; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D009474:Neurons / Q000166:cytology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000008:administration & dosage* / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D051020:bcl-X Protein
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C030325:anthrax toxin; D051020:bcl-X Protein