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Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease

Ming-Chang Chiang1, Hui-Mei Chen, Yi-Hsin Lee

  • 1Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan.

Human Molecular Genetics
|January 11, 2007
PubMed

Insights

Huntington's disease (HD) involves urea cycle deficiency and ammonia toxicity, worsening neurological symptoms. Protein-restricted diets improved urea cycle function, reduced ammonia, and ameliorated HD symptoms in mouse models.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene.
  • Urea cycle deficiency, marked by hyperammonemia, is a significant feature in HD mouse models.

Purpose of the Study:

  • To investigate the role of urea cycle deficiency in HD pathogenesis.
  • To explore the impact of mutant Huntingtin (Htt) on urea cycle enzyme regulation.
  • To evaluate the therapeutic potential of dietary interventions for HD.

Main Methods:

  • Utilized two mouse models of Huntington's disease.
  • Assessed urea cycle enzyme activity, ammonia levels, and C/EBPalpha transcription factor function.
  • Examined the interaction between mutant Htt, C/EBPalpha, and cofactors.
  • Investigated the effects of protein-restricted diets on HD pathology and symptoms.

Main Results:

  • HD mouse models exhibit urea cycle deficiency and hyperammonemia, potentially exacerbating neurological deficits.
  • Mutant Htt impairs C/EBPalpha function by disrupting cofactor interaction and promoting aggregation.
  • Protein-restricted diets restored C/EBPalpha activity, repaired urea cycle deficiency, reduced hyperammonemia, and improved motor function and Htt aggregate formation in HD mice.

Conclusions:

  • Urea cycle deficiency is a key pathological feature in HD, driven by impaired C/EBPalpha function due to mutant Htt.
  • Targeting urea cycle repair and ammonia detoxification presents a promising therapeutic strategy for Huntington's disease.
  • Dietary protein restriction demonstrates efficacy in ameliorating HD pathology and symptoms in preclinical models.

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