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

Abstract 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...

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Autores principales:	Kaly A. Mueller, Kelly E. Glajch, Megan N. Huizenga, Remi A. Wilson, Eric J. Granucci, Amanda M. Dios, Adelaide R. Tousley, Maria Iuliano, Elizabeth Weisman, Michael J. LaQuaglia, Marian DiFiglia, Kimberly Kegel-Gleason, Khashayar Vakili, Ghazaleh Sadri-Vakili
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cccd0dab16664adfba16dc950c90aec9
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spelling	oai:doaj.org-article:cccd0dab16664adfba16dc950c90aec92021-12-02T15:09:07ZHippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells10.1038/s41598-018-29319-42045-2322https://doaj.org/article/cccd0dab16664adfba16dc950c90aec92018-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-29319-4https://doaj.org/toc/2045-2322Abstract 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.Kaly A. MuellerKelly E. GlajchMegan N. HuizengaRemi A. WilsonEric J. GranucciAmanda M. DiosAdelaide R. TousleyMaria IulianoElizabeth WeismanMichael J. LaQuagliaMarian DiFigliaKimberly Kegel-GleasonKhashayar VakiliGhazaleh Sadri-VakiliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kaly A. Mueller Kelly E. Glajch Megan N. Huizenga Remi A. Wilson Eric J. Granucci Amanda M. Dios Adelaide R. Tousley Maria Iuliano Elizabeth Weisman Michael J. LaQuaglia Marian DiFiglia Kimberly Kegel-Gleason Khashayar Vakili Ghazaleh Sadri-Vakili Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells
description	Abstract 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.
format	article
author	Kaly A. Mueller Kelly E. Glajch Megan N. Huizenga Remi A. Wilson Eric J. Granucci Amanda M. Dios Adelaide R. Tousley Maria Iuliano Elizabeth Weisman Michael J. LaQuaglia Marian DiFiglia Kimberly Kegel-Gleason Khashayar Vakili Ghazaleh Sadri-Vakili
author_facet	Kaly A. Mueller Kelly E. Glajch Megan N. Huizenga Remi A. Wilson Eric J. Granucci Amanda M. Dios Adelaide R. Tousley Maria Iuliano Elizabeth Weisman Michael J. LaQuaglia Marian DiFiglia Kimberly Kegel-Gleason Khashayar Vakili Ghazaleh Sadri-Vakili
author_sort	Kaly A. Mueller
title	Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells
title_short	Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells
title_full	Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells
title_fullStr	Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells
title_full_unstemmed	Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells
title_sort	hippo signaling pathway dysregulation in human huntington’s disease brain and neuronal stem cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/cccd0dab16664adfba16dc950c90aec9
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Hippo Signaling Pathway Dysregulation in Human Huntington’s Disease Brain and Neuronal Stem Cells

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