Transcriptional Repression Induces a Slowly Progressive Atypical Neuronal Death Associated with Changes of YAP Isoforms and p73

• Published in: The Journal of cell biology 2006-02, Vol.172 (4), p.589-604
• Main Authors: Masataka Hoshino, Mei-ling Qi, Natsue Yoshimura, Miyashita, Tomoyuki, Kazuhiko Tagawa, Yo-ichi Wada, Enokido, Yasushi, Shigeki Marubuchi, Harjes, Phoebe, Nobutaka Arai, Kiyomitsu Oyanagi, Blandino, Giovanni, Sudol, Marius, Tina Rich, Kanazawa, Ichiro, Wanker, Erich E., Saitoe, Minoru, Okazawa, Hitoshi
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Amanitins - pharmacology; Amino Acid Sequence; Animals; Antibodies; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell death; Cell Death - genetics; Cell Survival - drug effects; Cells, Cultured; Cellular biology; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - drug effects; Down-Regulation - physiology; Drosophila melanogaster; Drosophila melanogaster - genetics; Embryo Research; Genes, Tumor Suppressor; HeLa cells; Humans; Huntington Disease - metabolism; Huntington Disease - pathology; Mice; Molecular Sequence Data; Mutagenesis, Insertional; Neurological disorders; Neurons; Neurons - metabolism; Neurons - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathology; Phosphoproteins - genetics; Protein isoforms; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Rats; Repression; RNA, Small Interfering - pharmacology; Small interfering RNA; Time Factors; Trans-Activators - drug effects; Trans-Activators - physiology; Transcription Factors; Transcription, Genetic - drug effects; Tumor Protein p73; Tumor Suppressor Proteins; Vacuoles
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200509132

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 (YAPΔCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPΔCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPΔCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophilo 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.