Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease.

Aaron D. Thome,David G. Standaert,Ashley S. Harms,Malú G. Tansey

doi:10.1371/journal.pone.0140566

Aaron D. Thome, David G. Standaert + Show 2 more

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https://doi.org/10.1371/journal.pone.0140566

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Journal: PloS one	Publication Date: Oct 15, 2015
Citations: 56	License type: CC BY 4.0

Affiliation: University of Alabama at Birmingham

Abstract

BackgroundParkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer’s disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation.MethodsTo examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn.ResultsWe observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn.ConclusionOur results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD.

Highlights

Parkinson disease (PD) is a common neurodegenerative movement disorder characterized by a progressive loss of dopamine producing neurons in the substantia nigra pars compacta (SNpc) and widespread intracellular aggregates of the protein alpha-synuclein (α-syn)
To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn
AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1

Summary

Introduction

Parkinson disease (PD) is a common neurodegenerative movement disorder characterized by a progressive loss of dopamine producing neurons in the substantia nigra pars compacta (SNpc) and widespread intracellular aggregates of the protein alpha-synuclein (α-syn). This protein is the principal component of Lewy bodies and Lewy neurites, the pathological hallmark of PD. Genome-wide association studies (GWAS) have linked the SNCA locus to PD susceptibility in sporadic disease [3] Together, these observations point to a central role for α-syn in the etiology of PD, the mechanisms by which α-syn initiates the disease and subsequent neurodegeneration remain uncertain. MHC class II is expressed on antigen presenting cells including microglia, and is critical for mounting an adaptive immune response by presenting antigen to CD4+ T cells

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