Gene transfer of baculoviral p35 by adenoviral vector protects human cerebral neurons from apoptosis.
Apoptosis plays an important role in neuronal cell death in both chronic and acute human neurological diseases, including ALS, Huntington's disease, cerebral ischemia, and HIV encephalopathy. We evaluated the ability of an extremely powerful antiapoptotic agent, baculoviral p35, to prevent apoptosis and cell death of human cerebral neurons that undergo severe neurotoxic changes in a culture system when treated with agents that are implicated in human neurological disorders, that is, tumor necrosis factor (TNFalpha) and the HIV proteins Tat and gp120. P35 is a potent broad-spectrum antiapoptotic protein derived from baculovirus, that inhibits nearly all caspases, and has other antiapoptotic actions as well. Adenoviral vectors expressing p35 (Ad. p35) or a control gene (lacZ) efficiently transduced human neurons. Treatment of control cultures with the toxic agents TNFalpha, TNFalpha plus Actinomycin D, or Tat and gp120, induced neurotoxicity and death of neurons. Transduction of neurons with Ad. p35 blocked apoptosis, and eliminated cell death due to TNFalpha, or Tat and gp120. Viral vector transfer of the p35 gene efficiently protects human neurons from TNFalpha, or Tat and gp120-induced apoptosis and cell death. These results suggest that p35 transduction of neurons by viral vectors could be therapeutically useful in the treatment of human neurodegenerative diseases.
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
Alexei
A
Miagkov
Jadwiga
J
Turchan
Avindra
A
Nath
Daniel B
DB
Drachman
D037881:Aborted Fetus; D000256:Adenoviridae; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers; D003609:Dactinomycin; D015696:Gene Products, tat; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006678:HIV; D015699:HIV Envelope Protein gp120; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D009422:Nervous System Diseases / Q000235:genetics / Q000628:therapy*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D017931:DNA Primers; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D051034:Inhibitor of Apoptosis Proteins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D054322:tat Gene Products, Human Immunodeficiency Virus; D003609:Dactinomycin