1. Academic Validation
  2. JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss

JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss

  • J Neuroinflammation. 2018 Jun 15;15(1):184. doi: 10.1186/s12974-018-1218-1.
Qing Wang 1 Qian He 1 Yifei Chen 1 Wei Shao 1 Chao Yuan 1 Yizheng Wang 2
Affiliations

Affiliations

  • 1 Center of Cognition and Brain Science, Beijing Institute of Medical Sciences, Beijing, 100000, People's Republic of China.
  • 2 National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, People's Republic of China. yzwang@ion.ac.cn.
Abstract

Background: Amplified inflammation is important for the progression of Parkinson's disease (PD). However, how this enhanced inflammation is regulated remains largely unknown. Deletion of DICER leads to progressive dopamine neuronal loss and induces gliosis. We hypothesized that the homeostasis of microglial DICER would be responsible for the amplified inflammation in the mouse model of PD.

Methods: The microglia or C57BL/6 mice were treated or injected with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+), respectively, for the model establishment. Microglia and astrocytes sorted by fluorescence-activated cell sorter (FACS) were assayed by quantitative Real-Time PCR, Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), immunohistofluorescence, and mass spectrometry.

Results: Microglial DICER was phosphorylated at serine 1456 by c-jun N-terminal kinase (JNK) and downregulated in response to 1-methyl-4-phenylpyridinium (MPP+), a causative agent in PD. Inhibition of JNK phosphorylation of DICER at serine 1456 rescued the MPP+-induced DICER degradation, suppressed microglial inflammatory process, and prevented the loss of tyrosine hydroxylase-expressing neurons in the mouse MPTP model.

Conclusions: JNK-mediated microglial DICER degradation potentiates inflammation to induce dopaminergic neuronal loss. Thus, preventing microglial DICER degradation could be a novel strategy for controlling neuroinflammation in PD.

Keywords

DICER; Degradation; Inflammation; Microglia; Phosphorylation.

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