A CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene, leading to an expanded polyglutamine tract.
• CAG repeat instability and somatic expansion in the brain are hypothesized to be crucial for HD pathogenesis.
• The DNA mismatch repair gene MSH3 is a therapeutic target due to its role in CAG repeat instability and lack of associated malignancies upon nullizygosity.

Purpose of the Study:

• To investigate the role of somatic CAG repeat expansion in HD pathogenesis.
• To determine the therapeutic potential of targeting MSH3 in an HD mouse model with a large CAG repeat expansion.

Main Methods:

• Utilized the zQ175 knock-in mouse model of HD, carrying an approximately (CAG)185 repeat expansion.
• Crossed the mutant huntingtin allele with heterozygous and homozygous Msh3 knockout backgrounds.
• Assessed the impact of MSH3 ablation on somatic CAG repeat expansion, huntingtin aggregation, and transcriptional dysregulation in the brain.

Main Results:

• Complete ablation of Msh3 prevented somatic CAG repeat expansion in both the brain and periphery.
• Reducing Msh3 by 50% decreased the rate of somatic expansion.
• Neither MSH3 ablation nor reduced MSH3 levels affected huntingtin aggregation or striatal transcriptional profiles in the zQ175 model, contrasting with models with shorter CAG repeats.

Conclusions:

• Somatic CAG repeat expansion in the brain is not required for the onset of molecular and neuropathological phenotypes in HD models with large CAG repeat expansions.
• Targeting MSH3 may not be beneficial for HD patients with large CAG repeat expansions, as further expansion does not accelerate disease progression.
• Therapeutic interventions targeting somatic instability in HD should be administered as early as possible, before significant expansion occurs.