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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\u2019s 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<jats:sup><jats:italic>Q111\/Q111<\/jats:italic><\/jats:sup> 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<jats:sup><jats:italic>Q111\/Q111<\/jats:italic><\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/s41598-018-29319-4","type":"journal-article","created":{"date-parts":[[2018,7,23]],"date-time":"2018-07-23T10:35:05Z","timestamp":1532342105000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Hippo Signaling Pathway Dysregulation in Human Huntington\u2019s Disease Brain and Neuronal Stem Cells"],"prefix":"10.1038","volume":"8","author":[{"given":"Kaly A.","family":"Mueller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly E.","family":"Glajch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan N.","family":"Huizenga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remi A.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Granucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M.","family":"Dios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaide R.","family":"Tousley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Iuliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Weisman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"LaQuaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"DiFiglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Kegel-Gleason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khashayar","family":"Vakili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghazaleh","family":"Sadri-Vakili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,7,27]]},"reference":[{"key":"29319_CR1","doi-asserted-by":"crossref","unstructured":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. The Huntington\u2019s Disease Collaborative Research Group. Cell 72, 971\u2013983 (1993).","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"29319_CR2","doi-asserted-by":"publisher","first-page":"pe48","DOI":"10.1126\/stke.2003.207.pe48","volume":"2003","author":"ME MacDonald","year":"2003","unstructured":"MacDonald, M. E. Huntingtin: alive and well and working in middle management. Sci STKE 2003, pe48, https:\/\/doi.org\/10.1126\/stke.2003.207.pe48 (2003).","journal-title":"Sci STKE"},{"key":"29319_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JHD-159001","volume":"4","author":"KE Glajch","year":"2015","unstructured":"Glajch, K. E. & Sadri-Vakili, G. Epigenetic Mechanisms Involved in Huntington\u2019s Disease Pathogenesis. J Huntingtons Dis 4, 1\u201315, https:\/\/doi.org\/10.3233\/JHD-159001 (2015).","journal-title":"J Huntingtons Dis"},{"key":"29319_CR4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/B978-0-444-52014-2.00003-3","volume":"100","author":"KN McFarland","year":"2011","unstructured":"McFarland, K. N. & Cha, J. H. Molecular biology of Huntington\u2019s disease. Handb Clin Neurol 100, 25\u201381, https:\/\/doi.org\/10.1016\/B978-0-444-52014-2.00003-3 (2011).","journal-title":"Handb Clin Neurol"},{"key":"29319_CR5","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","volume":"10","author":"CA Ross","year":"2011","unstructured":"Ross, C. A. & Tabrizi, S. J. Huntington\u2019s disease: from molecular pathogenesis to clinical treatment. 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