1. A novel form of necrosis, TRIAD, occurs in human Huntington's disease.
- Author
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Yamanishi E, Hasegawa K, Fujita K, Ichinose S, Yagishita S, Murata M, Tagawa K, Akashi T, Eishi Y, and Okazawa H
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Apoptosis physiology, Brain metabolism, Brain ultrastructure, Cell Cycle Proteins metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum ultrastructure, Gene Knock-In Techniques, Humans, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Phosphoproteins metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Transcription Factors, YAP-Signaling Proteins, Polo-Like Kinase 1, Huntington Disease metabolism, Huntington Disease pathology, Necrosis metabolism, Necrosis pathology, Neurons metabolism, Neurons ultrastructure
- Abstract
We previously reported transcriptional repression-induced atypical cell death of neuron (TRIAD), a new type of necrosis that is mainly regulated by Hippo pathway signaling and distinct from necroptosis regulated by RIP1/3 pathway. Here, we examined the ultrastructural and biochemical features of neuronal cell death in the brains of human HD patients in parallel with the similar analyses using mutant Htt-knock-in (Htt-KI) mice. LATS1 kinase, the critical regulator and marker of TRIAD, is actually activated in cortical neurons of postmortem human HD and of Htt-KI mouse brains, while apoptosis promoter kinase Plk1 was inactivated in human HD brains. Expression levels of YAP/YAPdeltaC were decreased in cortical neurons of human HD brains. Ultra-structural analyses revealed extreme enlargement of endoplasmic reticulum (ER), which characterizes TRIAD, in cortical neurons of human HD and those of Htt-KI mice. These biochemical and morphological results support that TRIAD occurs in human and mouse neurons under the HD pathology.
- Published
- 2017
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