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Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
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Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System

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Expression of expanded CAG transcripts triggers nucleolar stress in Huntington's disease

Ho Tsoi1, Ho Yin Edwin Chan

  • 1Laboratory of Drosophila Research, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

Cerebellum (London, England)
|January 15, 2013
PubMed

Insights

Expanded CAG RNA in polyglutamine diseases disrupts ribosome production by interfering with nucleolin binding, leading to nucleolar stress and cell death. This mechanism may be common in neurodegeneration.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Polyglutamine (polyQ) diseases result from expanded CAG repeats in disease genes.
  • Both expanded proteins and RNA transcripts contribute to polyQ neurodegeneration.
  • Mutant Huntingtin (Htt) transcripts interact with nucleolin (NCL), a key protein in ribosome biogenesis.

Purpose of the Study:

  • To investigate the mechanism by which mutant Htt transcripts cause toxicity in polyQ diseases.
  • To determine the effect of mutant Htt transcripts on nucleolin and ribosomal RNA (rRNA) transcription.
  • To explore the role of nucleolar stress in polyQ disease pathogenesis.

Main Methods:

  • Utilized the R6/2 HD transgenic mouse model.
  • Investigated the interaction between mutant Htt transcripts and nucleolin (NCL).
  • Assessed the impact on ribosomal RNA (rRNA) promoter methylation and transcription factor binding.
  • Analyzed the activation of the p53/mitochondria-dependent nucleolar stress pathway.

Main Results:

  • Mutant Htt transcripts bind to NCL, preventing its association with the rRNA promoter's Upstream Control Element (UCE).
  • This interaction leads to UCE hypermethylation, inhibiting transcription factor binding and down-regulating pre-45s rRNA transcription.
  • The p53/mitochondria-dependent nucleolar stress-induced cell death pathway is activated in polyQ diseases.

Conclusions:

  • Mutant Htt RNA-mediated disruption of NCL function and rRNA transcription is a key pathogenic mechanism in polyQ diseases.
  • Nucleolar stress is identified as a common pathway in polyglutamine diseases and potentially other neurodegenerative disorders like Alzheimer's disease.
  • Targeting nucleolar stress may offer a therapeutic strategy for a range of neurodegenerative conditions.

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