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MicroRNA-142 reduces monoamine oxidase A expression and activity in neuronal cells by downregulating SIRT1
Amrita Datta Chaudhuri1, Sowmya V Yelamanchili, Howard S Fox
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Abstract:
Aberrant expression of microRNAs (miRs) has been implicated in the pathogenesis of several neurodegenerative disorders. In HIV-associated neurocognitive disorders (HAND), miR-142 was found to be upregulated in neurons and myeloid cells in the brain. We investigated the downstream effects of chronic miR-142 upregulation in neuronal cells by comparing gene expression in stable clones of the human neuroblastoma cell line BE(2)M17 expressing miR-142 to controls. Microarray analysis revealed that miR-142 expression led to a reduction in monoamine oxidase (MAO) A mRNA, which was validated by qRT-PCR. In addition to the mRNA, the MAOA protein level and enzyme activity were also reduced. Examination of primary human neurons revealed that miR-142 expression indeed resulted in a downregulation of MAOA protein level. Although MAOA is not a direct target of miR-142, SIRT1, a key transcriptional upregulator of MAOA is, thus miR-142 downregulation of MAOA expression is indirect. MiR-142 induced decrease in MAOA expression and activity may contribute to the changes in dopaminergic neurotransmission reported in HAND.
Insights
Chronic upregulation of microRNA-142 (miR-142) in neurons reduces monoamine oxidase A (MAOA) expression and activity. This downregulation of MAOA may impact dopaminergic neurotransmission in HIV-associated neurocognitive disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Aberrant microRNA (miR) expression is linked to neurodegenerative diseases.
- In HIV-associated neurocognitive disorders (HAND), miR-142 is upregulated in brain cells.
Purpose of the Study:
- To investigate the effects of sustained miR-142 upregulation on neuronal gene expression.
- To determine the impact of miR-142 on monoamine oxidase A (MAOA) in neuronal cells.
Main Methods:
- Gene expression analysis using microarrays and qRT-PCR in human neuroblastoma cells (BE(2)M17) engineered to express miR-142.
- Assessment of MAOA protein levels and enzyme activity.
- Validation in primary human neurons.
Main Results:
- miR-142 upregulation significantly reduced MAOA mRNA levels.
- MAOA protein levels and enzyme activity were decreased in miR-142 expressing cells.
- miR-142 indirectly downregulates MAOA expression, potentially via SIRT1.
Conclusions:
- Chronic miR-142 upregulation in neurons leads to decreased MAOA expression and activity.
- This miR-142-mediated downregulation of MAOA may contribute to altered dopaminergic neurotransmission in HAND.
- Findings highlight a novel molecular mechanism in the pathogenesis of HAND.
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