title: Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis.
abstract: Neuroinflammation is one of the most striking hallmarks of amyotrophic lateral sclerosis (ALS). Nuclear factor-kappa B (NF-κB), a master regulator of inflammation, is upregulated in spinal cords of ALS patients and SOD1-G93A mice. In this study, we show that selective NF-κB inhibition in ALS astrocytes is not sufficient to rescue motor neuron (MN) death. However, the localization of NF-κB activity and subsequent deletion of NF-κB signaling in microglia rescued MNs from microglial-mediated death in vitro and extended survival in ALS mice by impairing proinflammatory microglial activation. Conversely, constitutive activation of NF-κB selectively in wild-type microglia induced gliosis and MN death in vitro and in vivo. Taken together, these data provide a mechanism by which microglia induce MN death in ALS and suggest a novel therapeutic target that can be modulated to slow the progression of ALS and possibly other neurodegenerative diseases by which microglial activation plays a role.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Frakes
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Haidet-Phillips
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Schmelzer
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Braun
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Miranda
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Ladner
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Bevan
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Brian.Kaspar@NationwideChildrens.org.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D016923:Cell Death / Q000502:physiology*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D016328:NF-kappa B; C109415:SOD1 G93A protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1