ASPP2 involvement in p53-mediated HIV-1 envelope glycoprotein gp120 neurotoxicity in mice cerebrocortical neurons

Sci Rep. 2016 Sep 14:6:33378. doi: 10.1038/srep33378.

Abstract

The mechanisms behind HIV-1-associated neurocognitive disorders are still unclear. Apoptosis-stimulating protein 2 of p53 (ASPP2) is a damage-inducible p53-binding protein that stimulates p53-mediated apoptosis and transactivates proapoptotic and cell cycle regulatory genes. It has been reported that ASPP2 has a specific regulatory function in the death of retinal ganglion cells and the development of Alzheimer's disease. In this study, we used p53 and ASPP2 knockout mice and primary cerebrocortical neuron culture to analyze the role of the interaction between ASPP2 with p53 in HIV-1 envelope glycoprotein gp120-induced neurotoxicity. The results showed that 10 ng/mL gp120 protein might stimulate p53 overexpression and translocation to the nucleus, and 30 ng/mL gp120 protein could stimulate both p53 and ASPP2 translocation to the nucleus, but only with p53 overexpression. The primary cultured neurons of p53(-/-)ASPP2(+/-) mice had a higher survival rate than p53(-/-) mice under gp120 protein stress. The interaction of ASPP2 with p53 induced by a high dose of gp120 stimulated Bax transcription and contributed to caspase-3 cleavage, and ASPP2-siRNA attenuated gp120 induced neuron death through inhibition of Bax expression. These results suggest that ASPP2 plays an important role in p53-mediated neuronal apoptosis under gp120 stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cerebral Cortex / pathology*
  • Genotype
  • HIV Envelope Protein gp120 / toxicity*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Neurotoxicity Syndromes / genetics
  • Neurotoxicity Syndromes / pathology*
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Transcription, Genetic / drug effects
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • HIV Envelope Protein gp120
  • RNA, Small Interfering
  • Trp53bp2 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • Caspase 3