title: Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease.
abstract: BACKGROUND
  Parkinson 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Thome
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Harms
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D055786:Gene Knockout Techniques; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D017628:Microglia / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology*; D010587:Phagocytosis; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D051844:alpha-Synuclein