title: 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.
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Gao
authors.affiliation: The Fourth General Surgery Division, Shandong Cancer Hospital, School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250022, China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Shan
authors.affiliation: The Fourth General Surgery Division, Shandong Cancer Hospital, School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250022, China.
authors.forename: Bishi
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Beijing Institute of Hepatology, Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China.
authors.forename: Luxin
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Department of Infectious Diseases, Beijing Institute of Hepatology, Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China. dexi0963@yahoo.com.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Beijing Institute of Hepatology, Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China. zhangyulin1968@126.com.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009705:Nucleosides / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D055815:Young Adult
chemical_list: C512709:DRAM1 protein, human; D008565:Membrane Proteins; D009705:Nucleosides; D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; Autophagy; DRAM; Neuronal toxicity; Nucleoside analog