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Potential New Drug Target for Huntington's Disease Identified

Key findings

  • Recent studies suggest that activation of mammalian sterile 20–like serine/threonine kinase 1/2 (MST1/2), an upstream regulator of yes-associated protein (YAP) in the Hippo pathway, is linked to neurodegeneration
  • Massachusetts General Hospital researchers demonstrated that levels of phosphorylated MST1/2 and phosphorylated YAP were increased in post-mortem cortex from patients with Huntington's disease (HD) as well as in a mouse model of HD
  • Inhibition of MST1/2, thereby increasing YAP activity, may confer neuroprotection in HD
  • Thus, increases in phosphorylated MST1/2 appear to reduce the nuclear activity of YAP, thereby causing neuronal death in HD

A significant challenge in developing therapies for Huntington's disease (HD) has been the lack of validated drug targets. Although the causative mutation in the disease is known, scientists have yet to identify a central pathogenic mechanism.

It is known, however, that transcriptional dysregulation is a key pathogenic process early in HD. Numerous genes are altered in patients with HD symptoms, and the changes have been recapitulated in multiple animal and cellular models. It remains unclear why these alterations in gene expression occur.

Ghazaleh Sadri-Vakili, MS, PhD, assistant in Neuroscience at Massachusetts General Hospital, and colleagues are attempting to identify transcriptional modifiers that may be involved in HD pathogenesis. One candidate is the Hippo signaling pathway, specifically its terminal effector component, the transcriptional activator yes-associated protein (YAP).

Previously, the Hippo signaling pathway has been linked to organ size regulation and tumor suppression. In Scientific Reports, Dr. Sadri-Vakili and her team describe evidence that Hippo signaling is dysregulated in HD, and they propose mechanisms whereby YAP nuclear activity is altered, suggesting an association with HD pathogenesis.

As background, the researchers explain that the effect of the Hippo pathway on organ size, cell proliferation and induction of apoptosis is mediated by activation of mammalian sterile 20–like serine/threonine kinase 1/2 (MST1/2), an upstream regulator of YAP. Specifically, phosphorylation of MST1/2 leads to phosphorylation of YAP and its subsequent degradation.

Once YAP is phosphorylated, it can no longer translocate to the nucleus or bind to its transcriptional coactivator (transcriptional enhancer activator domain, TEAD). Therefore, YAP loses its transcriptional activity.

Previous research has also determined that the activation of MST1/2 is linked to neurodegeneration. In HD, decreases in YAP have been observed in association with a form of cell death induced by alterations in transcription, as well as neuronal death induced by mutant huntingtin (Htt) protein.

In this paper, the researchers present new evidence about the role of the Hippo pathway in HD:

  • Phosphorylated MST1, the active form, was significantly increased in post-mortem human HD cortex and in the brains of a mouse model of HD
  • YAP nuclear localization was decreased in cortex and neuronal stem cells from HD patients
  • Phosphorylated YAP (the inactive form) was significantly increased in human HD cortex and in the brains of the knock-in mice
  • In human HD cortex, YAP interacted with Htt and the chaperone protein 14-3-3, but interactions were not altered in the presence of mutant Htt
  • YAP/TEAD interactions and expression of Hippo pathway genes were altered in human HD cortex

The findings suggest, the researchers say, that increases in MST1/2 may reduce the nuclear activity of YAP, thereby causing neuronal death in HD and that increases in YAP phosphorylation lead to decreases in nuclear YAP levels.

The authors conclude that inhibiting MST1/2, thereby increasing YAP activity, may offer neuroprotection in HD. Two possible approaches would be to use drugs that target the Hippo pathway or receptors upstream of the Hippo pathway, or to use genetic strategies such as knockdown of MST1/2 to decrease YAP phosphorylation and increase its nuclear localization.

Learn about the Sadri-Vakili Neuroepigenetics Laboratory

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In this video, Ghazaleh Sadri-Vakili, PhD, director of the NeuroEpigenetics Laboratory and the MassGeneral Institute of Neurodegenerative Disease, discusses her genetic research, specifically concerning neurodegenerative diseases like ALS and X-linked dystonia parkinsonism.