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MicroRNA profiling reveals new aspects of HIV neurodegeneration: caspase-6 regulates astrocyte survival
Farshid Noorbakhsh1, Rithwik Ramachandran, Nicola Barsby
1Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada.
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.
Insights
HIV encephalitis alters microRNA profiles in the brain, leading to increased caspase-6 expression and cell death. These findings reveal new mechanisms contributing to HIV-associated neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Virology
Background:
- MicroRNAs (miRNAs) regulate gene expression in health and disease.
- HIV encephalitis (HIVE) is a neuroinflammatory disorder caused by HIV infection.
- Understanding molecular changes in HIVE is crucial for developing treatments.
Purpose of the Study:
- To investigate miRNA expression alterations in HIVE.
- To identify miRNA targets involved in HIVE pathogenesis.
- To elucidate the role of caspase-6 in HIV-induced neurodegeneration.
Main Methods:
- Microarray analysis of miRNA profiles in HIVE and control brain tissue.
- Bioinformatic analysis for miRNA target prediction and gene ontology enrichment.
- Immunohistochemistry to detect caspase-6 expression in brain sections.
- In vitro studies using human astrocytes exposed to HIV Vpr protein.
- In vivo studies using Vpr transgenic mice.
Main Results:
- Differential miRNA expression was observed in HIVE brains.
- Down-regulated miRNAs targeted cell death-related genes, including caspase-6.
- HIVE brains showed increased caspase-6 transcripts and protein.
- HIV Vpr induced caspase-6 activation and cell injury in astrocytes.
- Vpr expression in mice led to astrocyte apoptosis and neurobehavioral deficits.
Conclusions:
- HIV infection significantly alters brain miRNA profiles.
- Dysregulation of cell death pathways, particularly involving caspase-6, contributes to HIVE.
- These findings highlight a novel mechanism of HIV-associated neurodegeneration.
