Abstract
HIV invasion of the central nervous system (CNS) in the majority of patients infected with HIV-1, leads to dysfunction and injury within the CNS, showing a variety of neurological symptoms which was broadly termed HIV-associated neurocognitive disorder (HAND). But the molecular mechanisms are not completely understood. It has been suggested that apoptosis and autophagic dysfunction in neurons may play an important role in the development of HAND. Previous studies have indicated that p53 may be involved in the onset of neurological disorder in AIDS. Apoptosis-stimulating protein of p53-2 (ASPP2), a p53-binding protein with specific function of inducing p53, has been reported to modulate autophagy. In the present study, we observed that gp120 induces autophagy and apoptosis in SH-SY5Y neuroblastoma cells. Adenovirus-mediated overexpression of ASPP2 significantly inhibited autophagy and apoptosis induced by low dose of gp120 protein (50 ng/mL), but induced autophagy and apoptosis when treated by high dose of gp120 protein (200 ng/mL). Further, ASPP2 knockdown attenuated autophagy and apoptosis induced by gp120.Conclusion: ASPP2 had different effects on the autophagy and apoptosis of neurons induced by different concentration of gp120 protein. It may be a potential therapeutic agent for HAND through modulating autophagy and apoptosis in CNS.
Highlights
HIV-1-associated neurocognitive disorder (HAND), known as neuroAIDS, occurs in one-third of HIV-1-infected individuals (Gendelman et al, 1997)
Postmortem brains with HIV-1 encephalitis exhibit increased autophagic proteins such as lysosomal membrane protein 1 (LAMP-1), autophagy-related gene (Atg)-5, Atg-7, Beclin 1, and LC3II when compared with the brains from HIV-infected persons without HIV-1 encephalitis or the control brains without HIV-infection, suggesting that the dysregulation of autophagy may be important in the pathogenesis of neuroAIDS and plays a important role in the early cognitive impairment and dementia in advanced AIDS (Zhou et al, 2011)
To examine the effect of ASSP2 on autophagy and apoptosis induced by gp120 (Abcam, USA), SH-SY5Y neuroblastoma cells were transduced with adenovirus overexpressing Apoptosis-stimulating protein of p53-2 (ASPP2) with GFP flag (GFP-ASPP2-rAd) or GFP (GFP-rAd) for 36 h
Summary
HIV-1-associated neurocognitive disorder (HAND), known as neuroAIDS, occurs in one-third of HIV-1-infected individuals (Gendelman et al, 1997). Postmortem brains with HIV-1 encephalitis exhibit increased autophagic proteins such as lysosomal membrane protein 1 (LAMP-1), autophagy-related gene (Atg)-5, Atg-7, Beclin 1, and LC3II when compared with the brains from HIV-infected persons without HIV-1 encephalitis or the control brains without HIV-infection, suggesting that the dysregulation of autophagy may be important in the pathogenesis of neuroAIDS and plays a important role in the early cognitive impairment and dementia in advanced AIDS (Zhou et al, 2011). Apoptosis-stimulating protein of p53-2 (ASPP2) is a p53binding protein that stimulates pro-apoptosis of p53 (Samuels-Lev et al, 2001), which plays a key role in gp120mediated neurotoxicity (Garden et al, 2004). We found that ASPP2 could be involved in the gp120 mediated neurotoxixity, potentially via modulating apoptosis and autophagy
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