Hippo Signaling Pathway Dysregulation in Human Huntington\u2019s Disease Brain and Neuronal Stem Cells

Kaly A Mueller,Ghazaleh Sadri-Vakili,Kelly E Glajch,Megan N Huizenga,Marian Difiglia,Adelaide R Tousley,Kimberly Kegel-Gleason,Amanda M Dios,Eric J Granucci,Michael J Laquaglia,Khashayar Vakili,Remi A Wilson,Maria Iuliano,Elizabeth Weisman

doi:10.1038/s41598-018-29319-4

Kaly A Mueller, Ghazaleh Sadri-Vakili + Show 12 more

Open Access

https://doi.org/10.1038/s41598-018-29319-4

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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 HdhQ111/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 HdhQ111/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.

Highlights

The Hippo signaling pathway is involved in organ size regulation and tumor suppression
There was a significant decrease in Yes-Associated Protein (YAP) nuclear localization in neurons in Huntington’s disease (HD) patients compared to control cortex as measured by co-localization with DAPI (p = 0.0020, MannWhitney U Test) (Fig. 1c)
These results indicate that while there is no significant difference in cytoplasmic YAP (p = 0.3095, Mann-Whitney U Test), there is a significant decrease in nuclear YAP levels in HD compared to control (p = 0.0152, Mann-Whitney U Test) (Fig. S3)

Summary

Introduction

The Hippo signaling pathway is involved in organ size regulation and tumor suppression. Recent studies from our laboratory as well as others have focused on identifying critical and novel transcriptional modifiers that may be involved in HD pathogenesis One such candidate is the Hippo signaling pathway, its terminal effector component, the transcriptional activator Yes-Associated Protein (YAP). In HD, decreases in YAP were linked to transcriptional repression-induced atypical cell death (TRIAD), a morphologically and biologically distinct form of cellular death induced by alterations in transcription[25], as well as mHtt-induced neuronal death termed ‘ballooning cell death’ (BCD)[26] Together these studies demonstrate that mHtt disrupts YAP-TEAD interactions and suggest that inhibiting Hippo signaling or increasing YAP nuclear activity may provide a new target for the development of treatments in HD.

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