title: Fractalkine over expression suppresses α-synuclein-mediated neurodegeneration.
abstract: In Parkinson's disease, α-synuclein is known to activate microglia and this activation has been proposed as one of the mechanisms of neurodegeneration. There are several signals produced by neurons that have an anti-inflammatory action on microglia, including CX3CL1 (fractalkine). We have shown that a soluble form of CX3CL1 is required to reduce neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that fractalkine agonism can reduce neuron loss in a 6-hydroxydopamine lesion model. Here, we show that fractalkine can reduce α-synuclein-mediated neurodegeneration in rats. Rats that received fractalkine showed abrogated loss of tyrosine hydroxylase and Neu-N staining. This was replicated in animals where we expressed fractalkine from astrocytes with the glial fibrillary acid protein (GFAP) promoter. Interestingly, we did not observe a reduction in MHCII expression suggesting that soluble fractalkine is likely altering the microglial state to a more neuroprotective one rather than reducing antigen presentation.
authors.affiliation: Molecular Pharmacology and Physiology Department, Byrd Alzheimer Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Nash
authors.affiliation: Molecular Pharmacology and Physiology Department, Byrd Alzheimer Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Moran
authors.affiliation: Molecular Pharmacology and Physiology Department, Byrd Alzheimer Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Finneran
authors.affiliation: James A. Haley Veterans Affairs Hospital, Research Service, Department of Neurosurgery and Brain Repair, and Center of Excellence for Aging and Brain Repair USF, Tampa, Florida, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Hudson
authors.affiliation: Molecular Pharmacology and Physiology Department, Byrd Alzheimer Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Molecular Pharmacology and Physiology Department, Byrd Alzheimer Institute, University of South Florida, Tampa, Florida, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
authors.affiliation: James A. Haley Veterans Affairs Hospital, Research Service, Department of Neurosurgery and Brain Repair, and Center of Excellence for Aging and Brain Repair USF, Tampa, Florida, USA.
authors.forename: Paula C
authors.initials: PC
authors.lastname: Bickford
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D017951:Antigen Presentation; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D054428:Chemokine CX3CL1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005904:Glial Fibrillary Acidic Protein; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D000949:Histocompatibility Antigens Class II; D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; C528900:glial fibrillary astrocytic protein, mouse; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase