Downregulation of miR-7116-5p in microglia by MPP+ sensitizes TNF-α production to induce dopaminergic neuron damage

Abstract

Activation of microglia resulting in exacerbated inflammation expression plays an important role in degeneration of dopaminergic (DA) neurons in the pathogenesis of Parkinson's disease (PD). However, how this enhanced inflammation is induced in microglia remains largely unclear. Here, in the mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP), we found that miR-7116-5p in microglia has a crucial role in this inflammation. 1-methyl-4-phenylpyridinium (MPP⁺) is uptaken by microglia through organic cation transporter 3 (OCT3) to downregulate miR-7116-5p, an miRNA found to target tumor necrosis factor alpha (TNF-α). Production of TNF-α in microglia is specifically potentiated by MPP⁺ via downregulation of miR-7116-5p to elicit subsequent inflammatory responses. Furthermore, enhancement of miR-7116-5p expression in microglia in mice inhibits the production of TNF-α and the activation of glia, and further prevents loss of DA neurons. Together, our studies suggest that MPP⁺ suppresses miR-7116-5p level in microglia and potentiates TNF-α production and inflammatory responses to contribute to DA neuron damage.

Main Points

• Microglia uptakes MPP⁺ through OCT3.
• MPP⁺ specifically potentiates the production of TNF-α in microglia through downregulation of miR-7116-5p, contributing to exacerbated inflammation expression and DA damage.

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