title: NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization.
abstract: Nuclear transcription factor-Y (NF-Y), a key regulator of cell-cycle progression, often loses its activity during differentiation into nonproliferative cells. In contrast, NF-Y is still active in mature, differentiated neurons, although its neuronal significance remains obscure. Here we show that conditional deletion of the subunit NF-YA in postmitotic mouse neurons induces progressive neurodegeneration with distinctive ubiquitin/p62 pathology; these proteins are not incorporated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic ER disorganization, that is, an aberrant increase in ribosome-free ER in the perinuclear region, without inducing ER stress response. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including Grp94 potentially involved in ER disorganization. We propose that NF-Y is involved in a unique regulation mechanism of ER organization in mature neurons and its disruption causes previously undescribed novel neuropathology accompanying abnormal ubiquitin/p62 accumulation.
authors.affiliation: 1] Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan [2] Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [3] Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [4] CREST (Core Research for Evolutionary Science and Technology), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: 1] Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [2] CREST (Core Research for Evolutionary Science and Technology), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Tosaki
authors.affiliation: 1] Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan [2] Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [3] Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [4] CREST (Core Research for Evolutionary Science and Technology), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: 1] Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan [2] Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [3] Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [4] CREST (Core Research for Evolutionary Science and Technology), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Matsumoto
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.affiliation: Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shimogori
authors.affiliation: Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: 1] Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan [2] Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [3] Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan [4] CREST (Core Research for Evolutionary Science and Technology), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D023081:CCAAT-Binding Factor; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; C018551:glucose-regulated proteins; C402244:nuclear factor Y