microRNA as a new agent for regulating neuronal glutathione synthesis and metabolism

Abstract

microRNA (miRNA) is a small non-coding RNA molecule that plays a role in the post-transcriptional regulation of gene expression. Recent evidence shows that miRNAs are involved in various diseases, including neurodegenerative diseases (NDs) such as: Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Amyotrophic lateral sclerosisand multiple system atrophy (MSA). The initiation and progression of NDs is generally considered to be induced by oxidative stress arising from an imbalance of oxidants and antioxidants. One of the most important antioxidants against oxidative stress is glutathione (GSH), which is a tripeptide composed of cysteine, glutamate and glycine. Among these precursor amino acids, cysteine is the determinant of neuronal GSH synthesis. Cysteine uptake in the neurons is mostly mediated by excitatory amino acid carrier 1 (EAAC1), a member of the sodium-dependent excitatory amino acid transporters. Interestingly, it has been reported that one miRNA, miR-96-5p, regulates the neuroprotective effect of GSH by directly regulating EAAC1 expression. Furthermore, the expressions of miR-96-5p and its target EAAC1 are specifically deregulated in the brains of patients with MSA, suggesting that deregulated miR-96-5p induces MSA via EAAC1 down-regulation. Since miR-96-5p regulation of EAAC1 expression and GSH level is indicated to be under circadian control, a greater understanding of rhythmic miRNA regulation could lead to the use of miRNA in chronotherapy for ND. In this review, we focus on the role of miRNA in the mechanism of GSH synthesis and metabolism; particularly with respect to a critical transport system of its rate-limiting substrate via EAAC1, as well as on the implications and chronotherapeutic potential of miRNA for NDs.

Keywords

• glutathione
• microRNA
• oxidative Stress
• EAAC1