title: Novel insights into role of miR-320a-VDAC1 axis in astrocyte-mediated neuronal damage in neuroAIDS.
abstract: Astroglia are indispensable component of the tripartite synapse ensheathing innumerous soma and synapses. Its proximity to neurons aids the regulation of neuronal functions, health and survival through dynamic neuroglia crosstalk. Susceptibility of astrocyte to HIV-1 infection and subsequent latency culminates in compromised neuronal health. The viral protein HIV-1 transactivator of transcription (Tat) is neurotoxic. HIV-1 Tat is detected in brain of AIDS patients even in cases where viral load is non-detectable due to successful HAART therapy. Recently, we demonstrated that HIV-1 Tat triggers excess ATP release from astrocytes that causes neuronal death by activating purinergic receptor system. Using well-characterized model system of human primary astrocytes and neurons, we probed into the molecular mechanism for enhanced ATP release in HIV-1 Tat affected astrocytes. HIV-1 Tat modulated the miRNA machinery in astrocytes and perturbed the levels of voltage dependent anion channel 1 (VDAC1), a channel present in the outer mitochondrial membrane and plasma membrane that regulates extracellular ATP release. Our studies with autopsy tissue sections also showed concordantly dysregulated VDAC1 and miR-320a levels in HIV-1 patients suffering from mild cognitive impairment (MCI). We report a novel molecular cascade of miRNA-mediated ATP release through regulation of VDAC1. Downregulation of VDAC1 either with miR-320a mimic or VDAC1 siRNA in HIV-1 Tat-affected astroglia could rescue the neurons from glia-mediated indirect death. Our findings reveal a novel upstream therapeutic target that could be employed to thwart the astroglia-mediated neurotoxicity in HIV-1 neuropathogenesis. GLIA 2017;65:250-263.
authors.affiliation: Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
authors.forename: Mahar
authors.initials: M
authors.lastname: Fatima
authors.affiliation: Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
authors.forename: Bharat
authors.initials: B
authors.lastname: Prajapati
authors.affiliation: Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
authors.forename: Kanza
authors.initials: K
authors.lastname: Saleem
authors.affiliation: Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
authors.forename: Rina
authors.initials: R
authors.lastname: Kumari
authors.affiliation: Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
authors.forename: Chitra
authors.initials: C
authors.lastname: Mohindar Singh Singal
authors.affiliation: Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D001344:Autopsy; D001921:Brain / Q000473:pathology / Q000821:virology; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000209:etiology / Q000821:virology; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D015658:HIV Infections / Q000150:complications / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology; D013997:Time Factors; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; C572916:MIRN320 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C494762:VDAC1 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D050995:Voltage-Dependent Anion Channel 1
keywords: ATP release; HIV-1 Tat; miRNA; neuroAIDS; voltage-dependent anion channel 1