title: MicroRNA profiling reveals new aspects of HIV neurodegeneration: caspase-6 regulates astrocyte survival.
abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules, which are known to regulate gene expression in physiological and pathological conditions. miRNA profiling was performed using brain tissue from patients with HIV encephalitis (HIVE), a neuroinflammatory/degenerative disorder caused by HIV infection of the brain. Microarray analysis showed differential expression of multiple miRNAs in HIVE compared to control brains. Target prediction and gene ontology enrichment analysis disclosed targeting of several gene families/biological processes by differentially expressed miRNAs (DEMs), with cell death-related genes, including caspase-6, showing a bias toward down-regulated DEMs. Consistent with the miRNA data, HIVE brains exhibited higher levels of caspase-6 transcripts compared with control patients. Immunohistochemical analysis showed localization of the cleaved form of caspase-6 in astrocytes in HIVE brain sections. Exposure of cultured human primary astrocytes to HIV viral protein R (Vpr) induced p53 up-regulation, loss of mitochondrial membrane potential, and caspase-6 activation followed by cell injury. Transgenic mice, expressing Vpr in microglial cells, demonstrated astrocyte apoptosis in brain, which was associated with caspase-6 activation and neurobehavioral abnormalities. Overall, these data point to previously unrecognized alterations in miRNA profile in the brain during HIV infection, which contribute to cell death through dysregulation of cell death machinery.
authors.affiliation: Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada.
authors.forename: Farshid
authors.initials: F
authors.lastname: Noorbakhsh
authors.forename: Rithwik
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Nicola
authors.initials: N
authors.lastname: Barsby
authors.forename: Kristofor K
authors.initials: KK
authors.lastname: Ellestad
authors.forename: Andrea
authors.initials: A
authors.lastname: LeBlanc
authors.forename: Peter
authors.initials: P
authors.lastname: Dickie
authors.forename: Glen
authors.initials: G
authors.lastname: Baker
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D015526:AIDS Dementia Complex / Q000209:etiology*; D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling; D053178:Caspase 6 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D005260:Female; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications* / Q000235:genetics; D015497:HIV-1; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger; D054325:vpr Gene Products, Human Immunodeficiency Virus; D053178:Caspase 6