Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

Indrapal N. Singh, Robin J. Goody, Celeste Dean, Nael M. Ahmad, Sarah E. Lutz, Pamela E. Knapp, Avindra Nath, Kurt F. Hauser

Research output: Contribution to journalArticle

Abstract

Human immunodeficiency virus-1 (HIV-1) infection affects the striatum, resulting in gliosis and neuronal losses. To determine whether HIV-1 proteins induce striatal neurotoxicity through an apoptotic mechanism, mouse striatal neurons isolated on embryonic day 15 and the effects of HIV-1 Tat1-72 and gp12O on survival were assessed in vitro. Mitochondrial release of cytochrome c, caspase-3 activation, and neuron survival, as well as an alternative apoptotic pathway involving endonuclease G (endo G), were assessed at 4 h, 24 h, 48 h, and/or 72 h using enzyme assays and immunoblotting. Both HIV-1 Tat and gp120 significantly increased caspase-3 activation in a concentration-dependent manner in striatal neurons at 4 h following continuous exposure in vitro. Tat1-72 and gp12O caused significant neuronal losses at 48 h and/or 72 h. Tat1-72 increased cytochrome c release, and caspase-3 and endo G activation at 4 h, 24 h, and/or 72 h. By contrast, gp120 increased caspase-3 activation, but failed to increase cytochrome c or endo G levels in the cytoplasm at 4 h, 24 h, and/or 72 h. The cell permeant caspase inhibitor Z-DEVD-FMK significantly attenuated gp120-induced, but not Tat1-72-induced, neuronal death, suggesting that gp120 acts in large part through the activation of caspase(s), whereas Tat1-72-induced neurotoxicity was accompanied by activating an alternative pathway involving endo G. Thus, although Tat1-72 and gp120 induced significant neurotoxicity, the nature of the apoptotic events preceding death differed. Collectively, our findings suggest that HIV-1 proteins are intrinsically toxic to striatal neurons and the pathogenesis is mediated through separate actions involving both caspase-3 and endo G.

Original languageEnglish (US)
Pages (from-to)141-151
Number of pages11
JournalJournal of neurovirology
Volume10
Issue number3
DOIs
StatePublished - Jun 1 2004

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Keywords

  • Caspase-3
  • Cytochrome c
  • Endonuclease G
  • Neurotoxicity

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

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