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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Animals
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Antigen Presentation
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Astrocytes / metabolism
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Astrocytes / pathology
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Chemokine CX3CL1 / agonists
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Chemokine CX3CL1 / genetics*
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Chemokine CX3CL1 / metabolism
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Dependovirus / genetics
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Gene Expression Regulation
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Genetic Therapy / methods*
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Genetic Vectors
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Glial Fibrillary Acidic Protein
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Histocompatibility Antigens Class II / genetics
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Male
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Mice
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Microglia / metabolism
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Microglia / pathology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / metabolism
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Neurons / pathology
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Oxidopamine
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Parkinson Disease, Secondary / chemically induced
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Parkinson Disease, Secondary / genetics
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Parkinson Disease, Secondary / metabolism
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Parkinson Disease, Secondary / therapy*
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Parkinsonian Disorders / genetics
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Parkinsonian Disorders / metabolism
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / therapy*
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Promoter Regions, Genetic
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Rats
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Signal Transduction
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Tyrosine 3-Monooxygenase / genetics
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Tyrosine 3-Monooxygenase / metabolism
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alpha-Synuclein / antagonists & inhibitors
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alpha-Synuclein / genetics*
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alpha-Synuclein / metabolism
Substances
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Chemokine CX3CL1
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Cx3cl1 protein, mouse
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Glial Fibrillary Acidic Protein
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Histocompatibility Antigens Class II
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Nerve Tissue Proteins
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alpha-Synuclein
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glial fibrillary astrocytic protein, mouse
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Oxidopamine
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Tyrosine 3-Monooxygenase