Abstract
MicroRNAs (miRNAs) have important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both human immunodeficiency virus (HIV)-associated dementia in humans and its monkey model simian immunodeficiency virus encephalitis (SIVE), we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. miR-21 can be induced in neurons by prolonged N-methyl--aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 specifically targets the mRNA of myocyte enhancer factor 2C (MEF2C), a transcription factor crucial for neuronal function, and reduces its expression. MEF2C is dramatically downregulated in neurons of HIV-associated dementia patients, as well as monkeys with SIVE. Together, this study elucidates a novel role for miR-21 in the brain, not only as a potential signature of neurological disease, but also as a crucial effector of HIV-induced neuronal dysfunction and neurodegeneration.
Highlights
We previously identified dysregulated expression of mRNAs in the brains of monkeys with simian immunodeficiency virus (SIV) encephalitis (SIVE) and humans with human immunodeficiency virus (HIV) encephalitis (HIVE), revealing altered expression of numerous genes including those expressed in neurons.[7,8]
We validated the expression change of these four miRNAs by real-time PCR on both regions of the monkey brains and in the human brain, and confirmed significant upregulation of three: miR-21, miR-1423p and miR-142-5p (Figure 1). miR-142 expression is largely confined to the hematopoietic system, whereas miR-21 expression has been found in a number of cell types and its altered expression linked to pathological changes. miR-21 was chosen for further analysis
We report for the first time the abnormal induction of miRNA in neurons in a neurocognitive disorder, HAD/HIVE, and its animal model, SIVE
Summary
HIV-associated neurocognitive disorders (HAND), varying in severity from an asymptomatic to a mild neurocognitive impairment and in its most serious form a debilitating dementia (HIV-associated dementia, HAD), develops in a subset of individuals infected with HIV-1.4 HAND results from an indirect neurotoxicity, as HIV infects macrophages and microglia, but not neurons, in the brain.[5,6] We previously identified dysregulated expression of mRNAs in the brains of monkeys with simian immunodeficiency virus (SIV) encephalitis (SIVE) and humans with HIV encephalitis (HIVE), revealing altered expression of numerous genes including those expressed in neurons.[7,8] Here, we describe the differential regulation of a crucial miRNA, miRNA-21, in the brains of individuals with SIVE/HIVE and its increased expression in neurons both in the brains of diseased subjects and in vitro upon N-methyl-D-aspartic acid (NMDA) receptor stimulation. Given the ability of miRNAs to modulate cellular mRNAs and proteins and cellular physiology, we identified a critical neuronal transcription factor, myocyte enhancer factor 2C (MEF2C), as a target of miR-21. In line with these results, we observe that MEF2C is downregulated at the protein level in the hippocampus and frontal cortex of SIVE/HIVE brains. These findings further underscore the importance of epigenetic changes caused by miRNA in context of neurological disease and highlights the regulatory loop, in which miRNAs function and their importance in neurodegenerative research. Initial candidate miRNAs shown were chosen because of greater than twofold change and a t-test result of Po0.05
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