Abstract
Glia play critical roles in maintaining the structure and function of the nervous system; however, the specific contribution that astroglia make to neurodegeneration in human disease states remains largely undefined. Here we use Alexander disease, a serious degenerative neurological disorder caused by astrocyte dysfunction, to identify glial-derived NO as a signalling molecule triggering astrocyte-mediated neuronal degeneration. We further find that NO acts through cGMP signalling in neurons to promote cell death. Glial cells themselves also degenerate, via the DNA damage response and p53. Our findings thus define a specific mechanism for glial-induced non-cell autonomous neuronal cell death, and identify a potential therapeutic target for reducing cellular toxicity in Alexander disease, and possibly other neurodegenerative disorders with glial dysfunction.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adolescent
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Adult
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Alexander Disease / genetics
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Alexander Disease / metabolism*
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Alexander Disease / pathology
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Animals
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Astrocytes / metabolism*
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Astrocytes / pathology
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Blotting, Western
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Cell Death
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Child
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Child, Preschool
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Disease Models, Animal
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Drosophila
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Female
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Glial Fibrillary Acidic Protein / genetics*
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Glial Fibrillary Acidic Protein / metabolism
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Humans
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In Situ Nick-End Labeling
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Infant
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Leukodystrophy, Metachromatic / metabolism
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Leukodystrophy, Metachromatic / pathology
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Male
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Mice
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Mice, Transgenic
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Microscopy, Confocal
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Neurodegenerative Diseases / metabolism
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Neurodegenerative Diseases / pathology
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Neuroglia / metabolism
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Neuroglia / pathology
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Neurons / metabolism*
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Neurons / pathology
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Nitric Oxide / metabolism*
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Organisms, Genetically Modified
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Oxidative Stress
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Reverse Transcriptase Polymerase Chain Reaction
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Young Adult
Substances
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Glial Fibrillary Acidic Protein
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Nitric Oxide