Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73.
Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73.
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DOI：
10.1083/jcb.200509132
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发表时间：
2006-02-13
期刊：
影响因子：
--
通讯作者：
Okazawa H
中科院分区：
文献类型：
--
作者：
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;Okazawa H
转录紊乱与多聚谷氨酰胺疾病（包括亨廷顿氏病（HD））的病理学有关。然而，目前还不清楚转录抑制是否会导致神经元死亡或死亡可能采取的形式。我们发现转录抑制诱导的神经元非典型死亡（TRIAD）与凋亡、坏死或自噬不同。与其他类型的细胞死亡相比，TRIAD的进展非常缓慢。基因表达谱分析揭示了全长yes相关蛋白（雅普）的减少，这是一种促进凋亡的p73辅因子，特异于TRIAD。此外，新的神经元特异性雅普亚型（雅普ΔCs）在TRIAD期间持续以显性负性方式抑制神经元死亡。雅普ΔCs和激活的p73共定位于HD患者和突变型亨廷顿（htt）转基因小鼠的纹状体神经元。雅普ΔCs还显著减弱了原代神经元和果蝇模型中Htt诱导的神经元死亡。总的来说，转录抑制诱导了一种新的神经元死亡的原型与雅普亚型和p73的变化，这可能是相关的HD病理。
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.
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