Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington's disease pathology.
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.
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Ying
Y
Mao
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Xigui
X
Chen
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Min
M
Xu
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Kyota
K
Fujita
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Kazumi
K
Motoki
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Toshikazu
T
Sasabe
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Hidenori
H
Homma
Department of Neurology, National Center of Neurology and Psychiatry, Ogawahigashimachi, Kodaira, Tokyo, Japan.
Miho
M
Murata
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Kazuhiko
K
Tagawa
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Takuya
T
Tamura
Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
Julia
J
Kaye
Gladstone Institute of Neurological Disease, San Francisco, CA, USA.|Departments of Neurology and Physiology, University of California, San Francisco, CA, USA
Steven
S
Finkbeiner
Oncogenetic and Epigenetic Unit, Regina Elena Cancer Institute, Rome, Italy.
Giovanni
G
Blandino
Mechanobiology Institute, National University of Singapore, Singapore, Republic of Singapore|Department of Physiology, National University of Singapore, Yong Loo Li School of Medicine, Singapore, Republic of Singapore|Institute of Molecular and Cell Biology (IMCB) A*STAR, Biopolis, Singapore, Republic of Singapore
Marius
M
Sudol
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.|Center for Brain Integration Research, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
Hitoshi
H
Okazawa
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000071058:Huntingtin Protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; C456659:YY1AP1 protein, human