Problems and solutions for the analysis of somatic CAG repeat expansion and their relationship to Huntington's disease toxicity

ABSTRACT

Huntington's Disease is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. Whether somatic expansion contributed to toxicity was unknown. From extensive work from multiple laboratories, it has been made clear that toxicity depended on length of the inherited allele, but whether preventing or delaying somatic repeat expansion in vivo would be beneficial was unknown, since the inherited disease allele was still expressed. In Budworth et al., we provided definitive evidence that suppressing the somatic expansion in mice substantially delays disease onset in littermates that inherit the same disease-length allele. This key discovery opens the door for therapeutic approaches targeted at stopping or shortening the CAG tract during life. The analysis was difficult and, at times, non-standard. Here, we take the opportunity to discuss the challenges, the analytical solutions, and to address some controversial issues with respect to expansion biology.

KEYWORDS:

• DNA repair
• huntington's Disease
• OGG1 DNA glycosylase
• oxidative DNA damage
• somatic expansion
• trinucleotides
• triplet repeat expansions

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Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This work was supported by National Institutes of Health grants ES020766 (to CTM), NS060115 (to CTM), and CA092584 (to CTM).