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.
Highlights
In the combined antiretroviral therapy era, HIV-1 associated neurocognitive disorders (HAND) have become an independent risk factor for AIDS mortality[1], and the total prevalence of HAND was approximately 37% in HIV-1 infected people[2]
Figure 1. gp[120] protein neurotoxicity. (A) The purity of primary cultured neurons was detected through immunofluorescence double staining using neuron-specific anti-microtubule association protein-2 (MAP-2) antibody and glial cell-specific antiGFAP antibody. (B) Morphologic change of neurons exposed to different gp[120] protein levels with propidium iodine (PI) and Calcein-AM double staining. (C) The correlation of gp[120] concentration and neuron apoptosis for 24 h. (D) The correlation of 30 ng/mL gp[120] exposure time and neuronal apoptosis
The purity of primary cultured neurons was detected through immunofluorescence double staining using neuron-specific anti-MAP-2 antibody and glial cell-specific anti-GFAP antibody
Summary
In the combined antiretroviral therapy (cART) era, HIV-1 associated neurocognitive disorders (HAND) have become an independent risk factor for AIDS mortality[1], and the total prevalence of HAND was approximately 37% in HIV-1 infected people[2]. The mechanism of HIV-1-induced neuronal damage and apoptosis is very complicated. Our previous in vitro study revealed that gp[120] could induce neuronal neurite damage and neuronal apoptosis in mice[10]. It was reported that p53 was upregulated in the glial cells of HAND patients[14] and was a key protein in gp120-mediated neurotoxicity[15]. Apoptosis stimulation of p53 protein 2 (ASPP2) is a damage-inducible p53-binding protein that stimulates p53-mediated apoptosis and transactivates proapoptotic and cell cycle regulatory genes. We investigated the role of ASPP2 and p53 on neurotoxicity in the presence of gp[120] protein using primary neuronal culture of p53−/−ASPP2+/− mice and p53−/− mice in vitro
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