Peli1 controls the survival of dopaminergic neurons through modulating microglia-mediated neuroinflammation

Dongfang Dai,Yan Wang,Yichuan Xiao,Chaoming Mao,Jing Xu,Jia Yuan

doi:10.1038/s41598-019-44573-w

Abstract

Chronic neuroinflammation is known to contributes to the toxicity of neurodegeneration of Parkinson’s disease (PD). However, the molecular and cellular mechanisms controlling inflammatory responses in the central nervous system remain poorly understood. Here we found that a E3 ubiquitin ligase Peli1 is dramatically induced only in the substantia nigra (SN) of the human and mouse PD brains. The ablation of Peli1 significantly suppressed LPS-induced production of neurotoxic mediators and proinflammatory cytokines in SN and in primary microglia, whereas Peli1 is dispensable for the inflammatory responses in astrocyte. Accordingly, Peli1 deficiency markedly inhibited neuron death induced by the conditioned medium from LPS-stimulated microglia. Mechanistical study suggested that Peli1 acts as a positive regulator of inflammatory response in microglia through activation of NF-κB and MAP kinase. Our results established Peli1 as a critical mediator in the regulation of microglial activation and neuroinflammation-induced death of dopaminergic neurons during PD pathogenesis, suggesting that targeting Peli1 may have therapeutic effect in neuroinflammation.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disease among people over 65 years old that causes the movement dysfunction, which is due to the death of tyrosine hydroxylase (TH)+ dopaminergic neurons in the substantia nigra (SN)[1,2]
Since we previously demonstrated that Peli[1] plays important roles in regulating the function of both central nervous system (CNS)-resident microglia and peripheral immune cells[19,20,22], so in order to examine the biological function of PELI1 during PD pathogenesis, we initially searched the public NCBI GEO database (GDS2519, GDS2821, GDS3128, GDS3129 and GDS4145) and examined the relative expression of PELI1 in SN, medullary regions, and peripheral blood mononuclear cells (PBMCs) that isolated from health donors (HD) and PD patients
We found that one dataset (GDS2821, GDS3128 and GDS3129) suggested that PELI1 expression is dramatically increased in the SN of PD patients as compared to that of HD (P = 0.0196, P = 0.0008, and P = 0.0451 Fig. 1a)

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disease among people over 65 years old that causes the movement dysfunction, which is due to the death of tyrosine hydroxylase (TH)+ dopaminergic neurons in the substantia nigra (SN)[1,2]. These factors like IL-1β can activate astrocyte to produce more neurotoxic mediators together with that produced by microglia, leading to the loss of dopaminergic neurons[14] These studies collectively suggested that bacteria infection may be a critical mediator to promote the disease onset and progression of PD. Our recent studies have indicated that Peli[1] protein is highly expressed in the brain and spinal cord, in which Peli[1] is predominantly expressed in microglia, but not in other CNS-resident cells like neuron, astrocytes and oligodendrocytes In such case, Peli[1] functions as an important mediator for microglia activation and contribute to the pathogenesis of multiple sclerosis and viral encephalitis[19,22]

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Results

Conclusion