Related Experiment Video
Updated: Aug 31, 2025
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
CAG Repeat Instability in the Peripheral and Central Nervous System of Transgenic Huntington's Disease Monkeys
In K Cho1,2, Faye Clever2, Gordon Hong2
1Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
Insights
Huntington's Disease (HD) CAG repeat instability varies by tissue in primate models. This CAG expansion correlates with gene expression, offering insights into disease mechanisms and potential therapeutic targets for this neurodegenerative disorder.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington's Disease (HD) is a fatal autosomal dominant neurodegenerative disorder.
- HD pathogenesis is linked to expanded CAG trinucleotide repeats (TNRs) in the Huntingtin gene (HTT).
- CAG repeat length influences disease severity, onset, and TNR instability, but mechanisms remain unclear.
Purpose of the Study:
- To investigate tissue-specific trinucleotide repeat (TNR) instability in transgenic nonhuman primate models of Huntington's Disease (HD).
- To explore the relationship between CAG repeat expansion, tissue susceptibility, and gene expression profiles in HD.
- To identify potential therapeutic targets by understanding CAG repeat instability.
Main Methods:
- Utilized transgenic nonhuman primate models (rHD1 and rHD7) of Huntington's Disease.
- Analyzed CAG repeat expansion across various tissues, including testis, liver, caudate, and putamen.
- Performed correlation analysis between CAG repeat expansion and the expression of key genes (CLU, TF, RPLP1, RPL13A).
Main Results:
- CAG repeat expansion was detected in all analyzed tissue samples from HD models.
- A similar profile of CAG repeat expansion and high instability was observed in testis, liver, caudate, and putamen.
- Significant correlations were found between CAG repeat expansion and the expression of CLU, TF, RPLP1, and RPL13A.
Conclusions:
- Tissue-specific CAG repeat instability is a key feature in Huntington's Disease primate models.
- CAG repeat expansion and instability are influenced by tissue type and repeat size.
- Gene expression patterns correlate with CAG repeat instability, providing potential avenues for therapeutic intervention in HD.
Abstract:
Huntington's Disease (HD) is an autosomal dominant disease that results in severe neurodegeneration with no cure. HD is caused by the expanded CAG trinucleotide repeat (TNR) on the Huntingtin gene (HTT). Although the somatic and germline expansion of the CAG repeats has been well-documented, the underlying mechanisms had not been fully delineated. Increased CAG repeat length is associated with a more severe phenotype, greater TNR instability, and earlier age of onset. The direct relationship between CAG repeat length and molecular pathogenesis makes TNR instability a useful measure of symptom severity and tissue susceptibility. Thus, we examined the tissue-specific TNR instability of transgenic nonhuman primate models of Huntington's disease. Our data show a similar profile of CAG repeat expansion in both rHD1 and rHD7, where high instability was observed in testis, liver, caudate, and putamen. CAG repeat expansion was observed in all tissue samples, and tissue- and CAG repeat size-dependent expansion was observed. Correlation analysis of CAG repeat expansion and the gene expression profile of four genes in different tissues, clusterin (CLU), transferrin (TF), ribosomal protein lateral stalk subunit P1 (RPLP1), and ribosomal protein L13a (RPL13A), showed a strong correlation with CAG repeat instability. Overall, our data, along with previously published studies, can be used for studying the biology of CAG repeat instability and identifying new therapeutic targets.
