title: Nitric oxide mediates glial-induced neurodegeneration in Alexander disease.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Waisman Center, Department of Comparative Biosciences, and School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hagemann
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kalwa
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Michel
authors.affiliation: Waisman Center, Department of Comparative Biosciences, and School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
mesh_terms: D000293:Adolescent; D000328:Adult; D038261:Alexander Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D016923:Cell Death; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004330:Drosophila; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007223:Infant; D007966:Leukodystrophy, Metachromatic / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D030781:Organisms, Genetically Modified; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D005904:Glial Fibrillary Acidic Protein; D009569:Nitric Oxide