Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington's disease pathology
Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington's disease pathology
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DOI：
10.1093/hmg/ddw303
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发表时间：
2016-11-01
影响因子：
3.5
通讯作者：
Okazawa, Hitoshi
中科院分区：
文献类型：
--
作者：
Mao, Ying;Chen, Xigui;Okazawa, Hitoshi
神经退行性疾病中的神经元细胞死亡尚不完全清楚。在这里，我们报道突变亨廷顿蛋白（Htt）是亨廷顿病（HD）的致病基因产物，它选择性地诱导了一种新的坏死细胞死亡形式，其中内质网（ER）扩大，细胞体不对称地膨胀并最终破裂。药理学和遗传学分析显示，坏死细胞死亡不同于RIP1/3通路依赖性的坏死坏死，而是由TEAD/ yap依赖性转录的功能缺陷介导的。此外，我们发现细胞周期调节因子Plk1通过YAP在Thr77位点的磷酸化，将YAP的相互作用伙伴从TEAD转移到p73，从而改变TEAD/YAP依赖性坏死和p73/YAP依赖性凋亡之间的平衡。双光子显微镜的体内ER成像检测到类似的ER扩大，病毒载体介导的YAP和Hippo通路的化学抑制剂如S1P的递送恢复了HD模型小鼠的ER不稳定和坏死。有趣的是，即使在症状出现后，S1P也能完全阻止HD模型小鼠运动功能的下降。总之，我们认为靶向TEAD/ yap -转录依赖性坏死（TRIAD）信号通路的方法可能导致HD的治疗发展。
Neuronal cell death in neurodegenerative diseases is not fully understood. Here we report that mutant huntingtin (Htt), a causative gene product of Huntington's diseases (HD) selectively induces a new form of necrotic cell death, in which endoplasmic reticulum (ER) enlarges and cell body asymmetrically balloons and finally ruptures. Pharmacological and genetic analyses revealed that the necrotic cell death is distinct from the RIP1/3 pathway-dependent necroptosis, but mediated by a functional deficiency of TEAD/YAP-dependent transcription. In addition, we revealed that a cell cycle regulator, Plk1, switches the balance between TEAD/YAP-dependent necrosis and p73/YAP-dependent apoptosis by shifting the interaction partner of YAP from TEAD to p73 through YAP phosphorylation at Thr77. In vivo ER imaging with two-photon microscopy detects similar ER enlargement, and viral vector-mediated delivery of YAP as well as chemical inhibitors of the Hippo pathway such as S1P recover the ER instability and necrosis in HD model mice. Intriguingly S1P completely stops the decline of motor function of HD model mice even after the onset of symptom. Collectively, we suggest approaches targeting the signalling pathway of TEAD/YAP-transcription-dependent necrosis (TRIAD) could lead to a therapeutic development against HD.