title: Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors.
abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N terminus of the Huntingtin protein (HTT). Reactive microglia and elevated cytokine levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms in microglia is unknown. Using genome-wide approaches, we found that expression of mutant Huntingtin (mHTT) in microglia promoted cell-autonomous pro-inflammatory transcriptional activation by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. We observed elevated levels of PU.1 and its target genes in the brains of mouse models and individuals with HD. Moreover, mHTT-expressing microglia exhibited an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest a cell-autonomous basis for enhanced microglia reactivity that may influence non-cell-autonomous HD pathogenesis.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Crotti
authors.affiliation: Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Bilal E
authors.initials: BE
authors.lastname: Kerman
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gosselin
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Ludwig Institute for Cancer Research, La Jolla, California, USA.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: Department of BioSciences and Center for Stem Cell Research, Università degli Studi di Milano, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zuccato
authors.affiliation: Department of BioSciences and Center for Stem Cell Research, Università degli Studi di Milano, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: 1] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [2] Ludwig Institute for Cancer Research, La Jolla, California, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: 1] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [2] Department of Medicine, University of California, La Jolla, San Diego, California, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics* / Q000502:physiology; D042622:DNA Repeat Expansion / Q000235:genetics; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins