Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington’s disease pathology

Abstract

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.

RETRACTED: Knockdown of Long Non-Coding RNA KCNQ1OT1 Restrained Glioma Cells’ Malignancy by Activating miR-370/CCNE2 Axis

“…Besides, a latest study shows CCNE2 is involved in regulation of Hippo pathway in breast cancer (Pegoraro et al, 2015). Hippo pathway is characterized as a tumor-suppressive axis, and plays important roles in tumor cellular process including proliferation, migration, invasion, and apoptosis (Alam et al, 2016; Atkins et al, 2016; Kemppainen et al, 2016; Mao et al, 2016). YAP is an important transcriptional activator and can be phosphorylated by Hippo pathway (Bouvier et al, 2016).…”

Amot regulates neuronal dendritic tree through Yap1

“…Our localization as well as functional experiments including RNAi-mediated silencing and neuron-specific deletion of Yap1 using conditional-knockout mice suggest Yap1 expression and function in neurons. This is consistent with previous reports of Okazawa and coworkers (Mao et al, 2016;Yamanishi et al, 2017) showing that Yap1 is largely expressed in mouse and human neurons positive for Map2 and NeuN.…”

“…Although Yap1 has been previously shown to be expressed in progenitor cells in the brain where it regulates proliferation, migration, and differentiation under both physiological and pathological conditions, the function of Yap1 has not yet been characterized in vertebrate neurons (Huang et al, 2016a;Huang et al, 2016b;Mao et al, 2016;Yamanishi et al, 2017).…”

The emerging role of Hippo signaling in neurodegeneration

“…Furthermore, it was revealed that a cell cycle regulator, Plk1, causes phosphorylation of YAP at Thr77, which is responsible for switching the interacting partner of YAP from TEAD to p73. This, in turn, represses the transcription of YAP–TEAD‐targeted cell survival genes and promotes the transcription of YAP–p73‐mediated, cell death‐related genes, suggesting an intricate combination of both TRIAD and apoptosis as a possible mechanism for cell death in HD (Ying Mao et al, ). A recent study by Mueller et al has also reported Hippo pathway dysregulation in HD.…”

“…Therapeutic approaches targeting the inhibition of Hippo pathway have also been shown to intervene HD. Pharmacological treatment with chemical inhibitors of the Hippo pathway like Sphingosine‐1‐phosphate (S1P) and lysophosphatidic acid (LPA) or exogenous delivery of YAP via viral vector has provided protection against neuronal cell death in primary neuronal cell culture model of HD and in Htt knockin HD mice model (Ying Mao et al, ). Considering that polyQ diseases like HD progress via nuclear restriction of YAP, a study on transgenic HD Drosophila model has shown that Yki overexpression rescues the PolyQ‐mediated toxicity in eye imaginal disks and restores functional vision.…”