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Updated: Apr 30, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Continuous and periodic expansion of CAG repeats in Huntington's disease R6/1 mice
Linda Møllersen1, Alexander D Rowe, Elisabeth Larsen
1Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Oslo University Hospital, Oslo, Norway.
Insights
Huntington's disease involves CAG repeat expansion in brain cells. This study reveals distinct expansion patterns in different tissues, with irreversible, periodic expansions in the brain unlike other organs.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder characterized by CAG repeat expansion in a specific gene.
- Somatic CAG expansion varies by organ in HD, with the brain showing the highest instability and neuropathology.
- Mechanisms of somatic CAG repeat instability are unclear, but DNA secondary structures during replication/repair are implicated.
Purpose of the Study:
- To investigate the rates and modes of somatic CAG repeat expansion in different tissues of Huntington's disease R6/1 mice.
- To elucidate the in vivo mechanisms underlying triplet repeat expansion in the brain versus other somatic tissues.
Main Methods:
- Analysis of CAG repeat expansion rates and patterns in various tissues of Huntington's disease R6/1 mouse model.
- Comparison of expansion dynamics between brain tissues (striatum, cortex) and peripheral tissues (tail).
Main Results:
- Somatic tissues like the tail exhibit continuous, small expansions and contractions, suggesting frequent single-repeat changes.
- Brain tissues, specifically the striatum and cortex, show dramatic, irreversible, and periodic CAG repeat expansions.
- These periodic expansion profiles in the brain are a novel finding not previously reported.
Conclusions:
- Mechanistically distinct processes drive CAG repeat expansion in different tissues of Huntington's disease models.
- The brain's unique, periodic expansion pattern may be linked to its specific neuropathology.
- Understanding these tissue-specific mechanisms is crucial for developing targeted HD therapies.
Abstract:
Huntington's disease (HD) is one of several neurodegenerative disorders caused by expansion of CAG repeats in a coding gene. Somatic CAG expansion rates in HD vary between organs, and the greatest instability is observed in the brain, correlating with neuropathology. The fundamental mechanisms of somatic CAG repeat instability are poorly understood, but locally formed secondary DNA structures generated during replication and/or repair are believed to underlie triplet repeat expansion. Recent studies in HD mice have demonstrated that mismatch repair (MMR) and base excision repair (BER) proteins are expansion inducing components in brain tissues. This study was designed to simultaneously investigate the rates and modes of expansion in different tissues of HD R6/1 mice in order to further understand the expansion mechanisms in vivo. We demonstrate continuous small expansions in most somatic tissues (exemplified by tail), which bear the signature of many short, probably single-repeat expansions and contractions occurring over time. In contrast, striatum and cortex display a dramatic--and apparently irreversible--periodic expansion. Expansion profiles displaying this kind of periodicity in the expansion process have not previously been reported. These in vivo findings imply that mechanistically distinct expansion processes occur in different tissues.
