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The Journal of Neuroscience, October 10, 2007, 27(41):11047-11055; doi:10.1523/JNEUROSCI.2733-07.2007
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Neurobiology of Disease
Human Immunodeficiency Virus-1/Surface Glycoprotein 120 Induces Apoptosis through RNA-Activated Protein Kinase Signaling in Neurons
Mehrdad Alirezaei,1 Debbie D. Watry,1 Claudia F. Flynn,1 William B. Kiosses,2 Eliezer Masliah,3 Bryan R. G. Williams,4 Marcus Kaul,5 Stuart A. Lipton,3,5 andHoward S. Fox1 1Molecular and Integrative Neurosciences Department and 2Core Microscopy Facility, The Scripps Research Institute, La Jolla, California 92037, 3Department of Neurosciences, University of California at San Diego, La Jolla, California 92039, 4Monash Institute of Medical Research, Monash University, Melbourne 3168, Victoria, Australia, and 5Center for Neuroscience, Stem Cell, and Aging Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037
Correspondence should be addressed to Howard S. Fox, The Scripps Research Institute, 10550 North Torrey Pines Road, SP30-2030, La Jolla, CA 92037. Email: hsfox{at}scripps.edu
Previous work has demonstrated that the surface glycoprotein (gp120) of human immunodeficiency virus-1 (HIV-1) can induce damage and apoptosis of neurons both in vitro and in vivo. In this report, we provide evidence that double-stranded RNA-activated protein kinase (PKR), a stress kinase, is involved in HIV/gp120-associated neurodegeneration. In cultures of mixed cortical cells, HIV/gp120 increased the protein level of PKR. Additionally, PKR was phosphorylated in neurons but not glia after exposure to gp120. The use of two independent pharmacological inhibitors of PKR activity abrogated neuronal cell death induced by gp120. Cortical neurons from PKR knock-out mice were significantly protected from neurotoxicity induced by gp120, further validating the pivotal proapoptotic function of PKR. gp120-induced phosphorylated PKR localized prominently to neuronal nuclei; PKR inhibition or the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] abrogated this effect. PKR inactivation also inhibited gp120-induced caspase-3 activation, consistent with its neuroprotective effect. Finally, brain tissue from individuals diagnosed with HIV-associated dementia (HAD), but not HIV infection alone, contained the activated form of PKR, which localized predominantly to neuronal nuclei. Together, these results identify PKR as a critical mediator of gp120 neurotoxicity, suggesting that activation of PKR contributes to the neuronal injury and cell death observed in HAD.
Key words: PKR; gp120; neurodegeneration; apoptosis; caspase-3; PACT
Received Feb. 22, 2007; revised Aug. 16, 2007; accepted Aug. 20, 2007.
Correspondence should be addressed to Howard S. Fox, The Scripps Research Institute, 10550 North Torrey Pines Road, SP30-2030, La Jolla, CA 92037. Email: hsfox{at}scripps.edu
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[Abstract] [Full Text] [PDF]
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