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ASPP2 involvement in p53-mediated HIV-1 envelope glycoprotein gp120 neurotoxicity in mice cerebrocortical neurons
Zhiying Liu1,2, Yunjin Zang3, Luxin Qiao1,2
1Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.
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.
Insights
Apoptosis-stimulating protein 2 of p53 (ASPP2) is involved in HIV-1 neurotoxicity. ASPP2 interacts with p53 to promote neuronal cell death under gp120 protein stress, suggesting a key role in HIV-1-associated neurocognitive disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Virology
Background:
- HIV-1-associated neurocognitive disorders (HAND) mechanisms remain unclear.
- Apoptosis-stimulating protein 2 of p53 (ASPP2) regulates p53-mediated apoptosis and is implicated in neurodegenerative diseases.
- ASPP2's role in HIV-1 neurotoxicity is not well understood.
Purpose of the Study:
- To investigate the role of the ASPP2-p53 interaction in HIV-1 envelope glycoprotein gp120-induced neurotoxicity.
- To analyze the impact of gp120 on p53 and ASPP2 expression and localization in neurons.
- To determine if ASPP2 contributes to gp120-induced neuronal apoptosis.
Main Methods:
- Utilized p53 and ASPP2 knockout mice models.
- Employed primary cerebrocortical neuron cultures.
- Administered varying concentrations of HIV-1 gp120 protein and ASPP2-siRNA.
Main Results:
- Low-dose gp120 (10 ng/mL) induced p53 overexpression and nuclear translocation.
- High-dose gp120 (30 ng/mL) induced p53 and ASPP2 nuclear translocation with p53 overexpression.
- Neurons from p53(-/-)ASPP2(+/-) mice showed increased survival compared to p53(-/-) mice under gp120 stress.
- ASPP2-p53 interaction induced by high-dose gp120 upregulated Bax transcription and caspase-3 cleavage.
- ASPP2-siRNA reduced gp120-induced neuronal death by inhibiting Bax expression.
Conclusions:
- ASPP2 plays a significant role in p53-mediated neuronal apoptosis under gp120 stress.
- The ASPP2-p53 interaction is a critical pathway in gp120-induced neurotoxicity.
- Targeting the ASPP2-p53 interaction may offer therapeutic strategies for HAND.
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