Study of neurodegenerative diseases and cell death in vivo finds new signaling pathway
After four years as a postdoctoral fellow at the University of Tokyo working on research into neuron synapse formation, I started my career in the Department of Neuropathology at TMDU. Our lab's theme is the elucidation of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease (HD).
Neurodegenerative diseases are characterized by slow progression compared with neuronal dysfunction and cell death. The typical cell deaths are apoptosis, necrosis and autophagic cell death. In 2006, our lab identified a new subtype of necrotic cell death named TRIAD (transcriptional repression-induced atypical cell death). In our research, we have captured images of TRIAD in the brain of live HD model mice. Through two-photon microscopy, we were able to observe the endoplasmic reticulum (ER) of neurons in the brain. In mutant HD-model mice, the ER enlarges, and the cell body forms an asymmetrical balloon shape until, finally, it ruptures.Pharmacological and genetic analyses revealed that this subtype of necrotic cell death is distinct from the RIP1/3 pathway-dependent necroptosis, as it is mediated by a functional deficiency of TEAD/YAP-dependent transcription.
In addition, we found 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 imaging of ER with two-photon microscopy detected the ER enlargement. Viral vector-mediated delivery of YAP, as well as chemical inhibitors of the Hippo pathway, such as S1P, repairs the ER instability and necrosis in HD model mice. Intriguingly, S1P completely stopped the decline of motor function in HD model mice even after the onset of symptoms. Collectively, we suggest that targeting the signaling pathway of TRIAD (TEAD/YAP-transcription-dependent necrosis) could lead to a therapeutic development to fight HD.