title: A novel form of necrosis, TRIAD, occurs in human Huntington's disease.
abstract: We previously reported transcriptional repression-induced atypical cell death of neuron (TRIAD), a new type of necrosis that is mainly regulated by Hippo pathway signaling and distinct from necroptosis regulated by RIP1/3 pathway. Here, we examined the ultrastructural and biochemical features of neuronal cell death in the brains of human HD patients in parallel with the similar analyses using mutant Htt-knock-in (Htt-KI) mice. LATS1 kinase, the critical regulator and marker of TRIAD, is actually activated in cortical neurons of postmortem human HD and of Htt-KI mouse brains, while apoptosis promoter kinase Plk1 was inactivated in human HD brains. Expression levels of YAP/YAPdeltaC were decreased in cortical neurons of human HD brains. Ultra-structural analyses revealed extreme enlargement of endoplasmic reticulum (ER), which characterizes TRIAD, in cortical neurons of human HD and those of Htt-KI mice. These biochemical and morphological results support that TRIAD occurs in human and mouse neurons under the HD pathology.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Yamanishi
authors.affiliation: Department of Neurology, National Hospital Organization, Sagamihara National Hospital, 18-1, Sakura-dai, Minami-ku, Yokosuka, 252-0392, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Shizuko
authors.initials: S
authors.lastname: Ichinose
authors.affiliation: Department of Neurology, National Hospital Organization, Sagamihara National Hospital, 18-1, Sakura-dai, Minami-ku, Yokosuka, 252-0392, Japan.
authors.forename: Saburo
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: Department of Neurology, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashimachi, Kodaira, Tokyo, 187-8551, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.affiliation: Department of Human Pathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Akashi
authors.affiliation: Department of Human Pathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. okazawa-tky@umin.ac.jp.|Department of Neuropathology, Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. okazawa-tky@umin.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D018797:Cell Cycle Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D055879:Gene Knock-In Techniques; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure*; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000097869:Polo-Like Kinase 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000097869:Polo-Like Kinase 1; C088374:YAP1 protein, human; C092745:LATS1 protein, human; C490501:Lats1 protein, mouse
keywords: Electron microscopy; Hippo pathway; Huntington’s disease; LATS; Necrosis; Neurodegeneration; TEAD; TRIAD; YAP