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

Sci Rep. 2018 Jul 27;8(1):11355. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Brain / pathology*
  • Disease Models, Animal
  • Hippo Signaling Pathway
  • Humans
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology*
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction*
  • Transcription Factors
  • Transcription, Genetic
  • YAP-Signaling Proteins


  • 14-3-3 Proteins
  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • RNA, Messenger
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Protein Serine-Threonine Kinases