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Updated: Mar 26, 2026
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
Metabolic disruption identified in the Huntington's disease transgenic sheep model
Renee R Handley1, Suzanne J Reid1, Stefano Patassini1
1Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
Insights
Huntington's disease (HD) disrupts metabolism, even before symptoms appear. A sheep model reveals distinct metabolic changes in the brain and liver, offering insights into early-stage HD.
Area of Science:
- Neuroscience
- Metabolomics
- Genetics
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder.
- It is caused by a CAG repeat expansion in the HTT gene.
- Current treatments do not slow disease progression.
Purpose of the Study:
- To investigate metabolic disruption in a transgenic sheep model of early-stage Huntington's disease.
- To compare metabolite profiles in different tissues of HD sheep and controls.
- To understand presymptomatic metabolic alterations in HD.
Main Methods:
- Utilized a transgenic sheep model (OVT73) exhibiting early molecular changes of HD.
- Performed quantitative metabolite profiling using gas chromatography-mass spectrometry.
- Analyzed tissue samples from the motor cortex, hippocampus, cerebellum, and liver.
Main Results:
- Significant differences in metabolite abundance were observed in the cerebellum and liver of transgenic sheep.
- Tissue-specific metabolic alterations included altered amino acids in the cerebellum and fatty acids in the liver.
- Increased metabolite correlations in transgenic cerebellum and liver suggest altered metabolic regulation.
Conclusions:
- The study demonstrates metabolic disruption in a presymptomatic sheep model of Huntington's disease.
- Findings suggest tissue-specific metabolic alterations, potentially indicating a hyper-metabolic state.
- This model provides valuable insights into the early, presymptomatic stages of HD metabolism.
Abstract:
Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.
