1. Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73.
- Author
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Hoshino M, Qi ML, Yoshimura N, Miyashita T, Tagawa K, Wada Y, Enokido Y, Marubuchi S, Harjes P, Arai N, Oyanagi K, Blandino G, Sudol M, Rich T, Kanazawa I, Wanker EE, Saitoe M, and Okazawa H
- Subjects
- Amanitins pharmacology, Amino Acid Sequence, Animals, Cell Death genetics, Cell Survival drug effects, Cells, Cultured, DNA-Binding Proteins genetics, Disease Models, Animal, Down-Regulation drug effects, Down-Regulation physiology, Drosophila melanogaster genetics, Embryo Research, Genes, Tumor Suppressor, Humans, Huntington Disease pathology, Mice, Molecular Sequence Data, Mutagenesis, Insertional, Neurons metabolism, Nuclear Proteins genetics, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Small Interfering pharmacology, Rats, Time Factors, Trans-Activators drug effects, Trans-Activators physiology, Transcription Factors, Tumor Protein p73, Tumor Suppressor Proteins, YAP-Signaling Proteins, Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, DNA-Binding Proteins metabolism, Huntington Disease metabolism, Neurons pathology, Nuclear Proteins metabolism, Phosphoproteins genetics, Transcription, Genetic drug effects
- 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.
- Published
- 2006
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