title: Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis.
abstract: Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: SungWon
authors.initials: S
authors.lastname: Song
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Miranda
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, 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, Ohio, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, 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, Ohio, 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, Ohio, USA.|Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Shibi
authors.initials: S
authors.lastname: Likhite
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Bevan
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.affiliation: Dept. of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McConnell
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.|Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, USA.|Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.|Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002102:Cadaver; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D054347:Receptors, KIR3DL2 / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: C062341:HLA-F antigens; D015395:Histocompatibility Antigens Class I; C515084:KIR3DL2 protein, human; D054347:Receptors, KIR3DL2; D013482:Superoxide Dismutase