MiR-425 deficiency promotes necroptosis and dopaminergic neurodegeneration in Parkinson\u2019s disease

Yong-Bo Hu,Hao Wang,Yong-Fang Zhang,Ru-Jing Ren,Qi Cheng,Hong-Zhuan Chen,Wan-Ying Huang,Hai-Lun Cui,Gang Wang

doi:10.1038/s41419-019-1809-5

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 conclusion, our study suggests that miR-425 deficiency triggers necroptosis of dopaminergic neurons, and targeting miR-425 in MPTP-treated mice restored dysfunctional dopaminergic neurodegeneration and ameliorated behavioral deficits. These findings identify brain delivery of miR-425 as a potential therapeutic approach for the treatment of PD.

Highlights

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN), and the causative mechanism is thought to be the activation of neuronal death[1]
A recent report found that administration of necrostatin-1 (Nec-1), a pharmacological inhibitor of necroptosis, effectively attenuated MPTP-induced dopaminergic neuron loss and mitochondrial toxicity, suggesting that necroptosis existed following MPTP treatment[25]
In the present study, following MPTP treatment for 5 consecutive days, immunofluorescence results revealed that receptor-interacting protein kinase 1 (RIPK1) and RIPK3 were increased in tyrosine hydroxylase (TH)-positive neurons in the mouse SN (Fig. 1e)

Summary

Introduction

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN), and the causative mechanism is thought to be the activation of neuronal death[1]. Different forms of cell death have been identified, their molecular mechanism and involvement in neurodegenerative diseases are not Necroptosis is a regulated process of cell death triggered by receptor-interacting protein kinase 1 (RIPK1)[5,6] and was first identified as a result of inflammation[4,7]. Necroptosis is initiated by activation of the TNFα receptor, followed by kinase activation of RIPK1 and RIPK38,9. Ser/Thr kinase, has an established role in mediating the deleterious mechanisms downstream of type I tumor necrosis factor α receptor (TNFR1)[10]. Activated RIPK1 and RIPK3 form the necrosome complex and recruit. The involvement of Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion