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.

Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes for Angiogenesis

“…Therefore, we evaluated the miRNA expression profile in C-MSC and C-MSC-Exo through miRNA microArray. Our results showed that miR-7116-5p is the most enriched, abundant miRNA in C-MSC-Exo compared to C-MSC, A report has shown that inhibition of miR-7116-5p level sin microglia enhances TNF-α production and inflammation, which lead to neuron damage [35], however, there is no report about the function of miR-7116-5p in cardiovascular and muscle systems. Bioinformatics pathway analysis shows that miR-7116-5p negatively regulates protein polyubiquitination.…”

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

“…Work in the MPTP model of PD provided compelling evidence that MPTP kills in both a cell‐autonomous manner through neuronal production of nitric oxide (NO) and activation of parthanatos and a non‐cell‐autonomous mechanism, through microglia production of NO through inducible NO synthase . Consistent with this notion, it was recently shown that MPP + can enter microglia through cation transporters, inducing oxidative stress and inflammation that ultimately exacerbate dopaminergic neurodegeneration . Growing recognition that glial involvement cannot be discounted in neuropathological investigations has thus inspired a reconsideration and examination of existing literature on PD models and mechanisms.…”

“…49 Consistent with this notion, it was recently shown that MPP + can enter microglia through cation transporters, inducing oxidative stress and inflammation that ultimately exacerbate dopaminergic neurodegeneration. 50 Growing recognition that glial involvement cannot be discounted in neuropathological investigations has thus inspired a reconsideration and examination of existing literature on PD models and mechanisms.…”

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

“…Microglial activation and inhibition of microglial activation is tightly regulated by a number of microRNAs including pro-inflammatory mir-155 and mir-204 as well as anti-inflammatory mir-203, mir-181c and mir-424 (Cardoso et al, 2012; Li L. et al, 2015). More recently, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model, a study has shown that 1-methyl-4-phenylpyridinium (MPP + ) downregulates mir-7116-5p in microglia and potentiates TNF-α production and inflammatory responses leading to DA neuron damage (He et al, 2017). …”