Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells

• Published in: Scientific reports Vol. 8; no. 1; pp. 11355 - 13
• Main Authors: Mueller, Kaly A., Glajch, Kelly E., Huizenga, Megan N., Wilson, Remi A., Granucci, Eric J., Dios, Amanda M., Tousley, Adelaide R., Iuliano, Maria, Weisman, Elizabeth, LaQuaglia, Michael J., DiFiglia, Marian, Kegel-Gleason, Kimberly, Vakili, Khashayar, Sadri-Vakili, Ghazaleh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 13/95; 14-3-3 protein; 14-3-3 Proteins - metabolism; 14/63; 38; 38/39; 38/77; 38/90; 631/378; 631/378/1934; 64; 64/60; 82; 82/29; 82/80; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autopsy; Brain - pathology; Brain stem; Disease Models, Animal; Humanities and Social Sciences; Humans; Huntingtin; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Kinases; Localization; multidisciplinary; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurodegeneration; Oxidative stress; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Signal Transduction; Stem cell transplantation; Stem cells; Transcription; Transcription Factors; Transcription, Genetic; Trinucleotide repeats; Tumor suppression; Tumorigenesis; Yes-associated protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-29319-4

The Hippo signaling pathway is involved in organ size regulation and tumor suppression. Although inhibition of Hippo leads to tumorigenesis, activation of Hippo may play a role in neurodegeneration. Specifically, activation of the upstream regulator, mammalian sterile 20 (STE20)-like kinase 1 (MST1), reduces activity of the transcriptional co-activator Yes-Associated Protein (YAP), thereby mediating oxidative stress-induced neuronal death. Here, we investigated the possible role of this pathway in Huntington’s disease (HD) pathogenesis. Our results demonstrate a significant increase in phosphorylated MST1, the active form, in post-mortem HD cortex and in the brains of CAG knock-in Hdh Q111/Q111 mice. YAP nuclear localization was also decreased in HD post-mortem cortex and in neuronal stem cells derived from HD patients. Moreover, there was a significant increase in phosphorylated YAP, the inactive form, in HD post-mortem cortex and in Hdh Q111/Q111 brain. In addition, YAP was found to interact with huntingtin (Htt) and the chaperone 14-3-3, however this interaction was not altered in the presence of mutant Htt. Lastly, YAP/TEAD interactions and expression of Hippo pathway genes were altered in HD. Together, these results demonstrate that activation of MST1 together with a decrease in nuclear YAP could significantly contribute to transcriptional dysregulation in HD.