miR-425 deficiency promotes necroptosis and dopaminergic neurodegeneration in Parkinson's disease

Cell Death & Disease
Yong-Bo HuGang Wang

Abstract

A major hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra, and the causative mechanism is thought to be the activation of programmed neuronal death. Necroptosis is a regulated process of cell death triggered by RIPK1. Although the pathophysiology of PD has been studied extensively, the cellular mechanism underlying dopaminergic neuron death remains unclear. In this study, we detected a specific miRNA, miR-425, in response to MPTP toxicity and dopaminergic degeneration. In MPTP-treated mice, we observed necroptosis activation and miR-425 deficiency in the substantia nigra, which is correlated with dopaminergic neuron loss. This miRNA targeted RIPK1 transcripts and promoted the phosphorylation of MLKL and necroptosis. Similarly, in the brains of PD patients, miR-425 deficiency and necroptosis activation were also confirmed in dopaminergic neuron. Furthermore, we found that genetic knockdown of miR-425 aggravated MPTP-induced motor deficits and dopaminergic neurodegeneration via early upregulation of necroptotic genes. Intracerebral miR-425 mimics (AgomiR-425) treatment attenuated necroptosis activation and dopaminergic neuron loss, and improved locomotor behaviors. In conclus...Continue Reading

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Jun 23, 2020·Metallomics : Integrated Biometal Science·Jiawen CuiShiwen Xu
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Datasets Mentioned

BETA
GSE7707

Methods Mentioned

BETA
genotyping
transfections
protein assay
enzyme-linked
transfection
ELISA
RNA-seq
transmission electron microscopy

Software Mentioned

ImageJ
SuperMaze
GraphPad Prism
GSEA
R
miRbase
Targetscan

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