Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73

Masataka Hoshino, Mei Ling Qi, Natsue Yoshimura, Tomoyuki Miyashita, Kazuhiko Tagawa, Yo Ichi Wada, Yasushi Enokido, Shigeki Marubuchi, Phoebe Harjes, Nobutaka Arai, Kiyomitsu Oyanagi, Giovanni Blandino, Marius Sudol, Tina Rich, Ichiro Kanazawa, Erich E. Wanker, Minoru Saitoe, Hitoshi Okazawa

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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 (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 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.

Original languageEnglish
Pages (from-to)589-604
Number of pages16
JournalJournal of Cell Biology
Volume172
Issue number4
DOIs
Publication statusPublished - Feb 13 2006

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Hoshino, M., Qi, M. L., Yoshimura, N., Miyashita, T., Tagawa, K., Wada, Y. I., Enokido, Y., Marubuchi, S., Harjes, P., Arai, N., Oyanagi, K., Blandino, G., Sudol, M., Rich, T., Kanazawa, I., Wanker, E. E., Saitoe, M., & Okazawa, H. (2006). Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73. Journal of Cell Biology, 172(4), 589-604. https://doi.org/10.1083/jcb.200509132