MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease

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.

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

“…miRNA dysregulation has been associated with several chronic inflammatory diseases, such as inflammatory bowel disease (9), experimental autoimmune encephalomyelitis (10), multiple sclerosis (11), and rheumatoid arthritis (12). Lately, the enhanced expression of miR-21 (13) and miR-142 (14) was correlated with macrophage activation and encephalitis in the brain of SIV-infected rhesus macaques. Focusing on the GI tract, an important site of CD4 ϩ T-cell depletion and HIV/SIV replication, we (15,16) and others (17) reported significant miRNA dysregulation in intact colon during SIV infection.…”

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

“…These findings also suggest that the protective effects of cannabinoids may also be mediated by similar regulatory factors/mechanisms (epigenetic) that need to be further investigated and identified, especially as they relate to HIV infection. For instance, several in vitro studies have shown altered miRNA expression in response to HIV infection (30)(31)(32)(33)(34), and recent miRNA profiling studies performed on brain (35) and plasma samples (36) provide strong evidence of their dysregulation during SIV infection. In addition, we recently reported miR-190b to be significantly upregulated in the intestine at all stages of SIV infection (37) and that viral replication rather than infection-related inflammatory responses induced miR-190b upregulation (37).…”

Myocyte Enhancer Factor-2 (MEF2) in Diseases of Central Nervous System: A Mini Review

“…In dementia patients infected with human immunodeficiency virus (HIV), neuronal MEF2C is downregulated by NMDA-induced activation of microRNA-21. [35] NMDA-induced excitotoxicity in cortical neurons is considered a major cause of dementia diseases due to oxidative stress and in vivo focal stroke, leading to the activation of caspase-3/7 and subsequent cleavage of MEF2A, 2C, and 2D isoforms. Ultimately, these changes result in neuronal apoptosis, which can be prevented by transfection of constitutively active MEF2 (MEF2C-CA).…”