Downregulation of miR-7116-5p in microglia by MPP1 sensitizes TNF-α production to induce dopaminergic neuron damage

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-alpha). Production of TNF-alpha in microglia is specifically potentiated by MPP1 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-alpha and the activation of glia, and further prevents loss of DA neurons. Together, our studies suggest that MPP1 suppresses miR-7116-5p level in microglia and potentiates TNF-alpha production and inflammatory responses to contribute to DA neuron damage.