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¹ Department of Neuropathology, Medical Research Institute and Center of Excellence Program for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
² Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan
³ Neuroproteomics, Max-Delbrück Center for Molecular Medicine, 13092 Berlin, Germany
⁴ Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy
⁵ Weis Center for Research, Geisinger Clinic, Danville, PA 17822
⁶ Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England, UK
⁷ National Center for Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan
⁸ Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawagoe, Saitama 332-0012, Japan

Correspondence to Hitoshi Okazawa: okazawa-tky{at}umin.ac.jp

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 (YAPCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPCs 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.

Abbreviations used in this paper: AMA, -amanitin; CDDP, cisplatin; FL-YAP, full-length YAP; HD, Huntington's disease; Pol II, polymerase II; polyQ, polyglutamine; siRNA, short inhibitory RNA; TRIAD, transcriptional repression-induced atypical death; YAP, yes-associated protein.

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