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Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP

Masataka Hoshino1, Mei-ling Qi, Natsue Yoshimura

  • 1Department of Neuropathology, Medical Research Institute and Center of Excellence Program for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

The Journal of Cell Biology
|February 8, 2006
PubMed

Insights

Transcriptional repression causes a novel, slow neuronal death (TRIAD) in Huntington's disease (HD) models. This process involves changes in yes-associated protein (YAP) isoforms and p73, distinct from known cell death pathways.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Transcriptional disturbance is a key factor in polyglutamine diseases like Huntington's disease (HD).
  • The specific mechanisms and forms of neuronal death resulting from transcriptional repression remain largely unknown.
  • Existing knowledge does not clarify if transcriptional repression directly causes neuronal death or its characteristics.

Purpose of the Study:

  • To investigate whether transcriptional repression leads to neuronal death.
  • To characterize the specific form of neuronal death induced by transcriptional repression.
  • To explore the molecular players involved in this novel cell death pathway and its relevance to HD.

Main Methods:

  • Induction of transcriptional repression in neuronal models.
  • Comparative analysis of cell death morphology and progression (TRIAD vs. apoptosis, necrosis, autophagy).
  • Gene expression profiling to identify specific molecular changes, focusing on yes-associated protein (YAP) and p73.
  • Validation in Huntington's disease patient samples and animal models (mutant huntingtin transgenic mice, Drosophila melanogaster).

Main Results:

  • A novel form of neuronal death, termed transcriptional repression-induced atypical death (TRIAD), was identified.
  • TRIAD exhibits a significantly slower progression compared to apoptosis, necrosis, or autophagy.
  • TRIAD is characterized by the reduction of full-length yes-associated protein (YAP) and the sustained presence of neuron-specific YAP isoforms (YAPDeltaCs).
  • YAPDeltaCs act in a dominant-negative manner to suppress neuronal death.
  • Activated p73 and YAPDeltaCs were found in striatal neurons of HD patients and mouse models.
  • YAPDeltaCs demonstrated a protective effect against mutant huntingtin-induced neuronal death in experimental models.

Conclusions:

  • Transcriptional repression can induce a novel prototype of neuronal death (TRIAD).
  • TRIAD is mechanistically linked to alterations in YAP isoforms and p73 activity.
  • These findings suggest a potential role for TRIAD and associated molecular changes in the pathology of Huntington's disease.

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