DRAM Is Involved in Regulating Nucleoside Analog-Induced Neuronal Autophagy in a p53-Independent Manner.

Abstract

The widespread use of combined anti-retroviral therapy (cART) has not decreased the prevalence of HIV-1-associated neurocognitive disorder (HAND), a type of neurodegenerative disease, even though cART effectively inhibits virus colonization in the central nervous system. Therefore, anti-retroviral agents cannot be fully excluded from the pathogenesis of HAND. Our previous study reported that long-term nucleoside analogue (NA) exposure induced mitochondrial toxicity in the cortical neurons of HAND patients and mice, but the exact mechanism of NA-associated neurotoxicity has remained unclear. Alteration of autophagy can result in protein aggregation and the accumulation of dysfunctional organelles, which are hallmarks of some neurodegenerative diseases. In this study, we first found increased autophagy in cortical autopsy specimens of AIDS patients. We then found that a low dose of NAs could stimulate autophagy in primary cultured neurons, while a high dose of NAs could induce only neuronal apoptosis. The level of NA-induced Bcl-2 and Bax expressions determined whether neuronal autophagy or apoptosis occurred. Furthermore, the level of NA-induced neuronal apoptosis correlated with the dysfunction of cellular DNA polymerase gamma. Damage-regulated autophagy modulator (DRAM) overexpression was also involved in NA-induced neuronal autophagy. p53 played a role in the regulation of NA-induced neuronal apoptosis, but its role in NA-associated neuronal autophagy was uncertain. Our results suggest that DRAM is involved in the regulation of NA-induced neuronal autophagy in a p53-independent manner. Further research is needed to investigate the underlying mechanism.