title: Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73.
abstract: Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPDeltaCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPDeltaCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPDeltaCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology.
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center of Excellence Program for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Hoshino
authors.forename: Mei-ling
authors.initials: ML
authors.lastname: Qi
authors.forename: Natsue
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miyashita
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Wada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Enokido
authors.forename: Shigeki
authors.initials: S
authors.lastname: Marubuchi
authors.forename: Phoebe
authors.initials: P
authors.lastname: Harjes
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Arai
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Oyanagi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.forename: Tina
authors.initials: T
authors.lastname: Rich
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kanazawa
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Minoru
authors.initials: M
authors.lastname: Saitoe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000546:Amanitins / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004331:Drosophila melanogaster / Q000235:genetics; D033041:Embryo Research; D016147:Genes, Tumor Suppressor; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D015534:Trans-Activators / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000546:Amanitins; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C509425:Yap1 protein, rat