A novel form of necrosis, TRIAD, occurs in human Huntington's disease

• Published in: Acta neuropathologica communications Vol. 5; no. 1; p. 19
• Main Authors: Yamanishi, Emiko, Hasegawa, Kazuko, Fujita, Kyota, Ichinose, Shizuko, Yagishita, Saburo, Murata, Miho, Tagawa, Kazuhiko, Akashi, Takumi, Eishi, Yoshinobu, Okazawa, Hitoshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08.03.2017; BioMed Central
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Amyotrophic lateral sclerosis; Animals; Apoptosis; Apoptosis - physiology; Brain - metabolism; Brain - ultrastructure; Care and treatment; Cell Cycle Proteins - metabolism; Cell death; Development and progression; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Gene Knock-In Techniques; Genes; Genetic aspects; Health aspects; Humans; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Kinases; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Necrosis; Necrosis - metabolism; Necrosis - pathology; Neurodegeneration; Neurons; Neurons - metabolism; Neurons - ultrastructure; Phosphoproteins - metabolism; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Psychological aspects; Transcription Factors; YAP-Signaling Proteins; United Kingdom > UK; United States > US; Hippo pathway; TEAD; Neurodegeneration; LATS; TRIAD; YAP; Huntington’s disease; Electron microscopy; Necrosis
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-017-0420-1

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.