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, 11 (8), e1005409
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Putting the Brakes on Huntington Disease in a Mouse Experimental Model

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Putting the Brakes on Huntington Disease in a Mouse Experimental Model

Jane C Kim et al. PLoS Genet.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Inhibiting somatic expansions delays onset of disease in a Huntington mouse model.
(A) Expanded (CAG)n repeats are more susceptible to undergoing further expansions, contributing to two distinct aspects of their instability. Intergenerational transmission (vertical axis) is the general increase in repeat length (m) from parent to offspring, which has been found to be dependent on MutSβ in mice. Somatic expansions (horizontal axis) are an increase in repeat length beyond the inherited length throughout the lifetime of an individual (x) and are dependent on both MutSβ and 8-oxoguanine glycosylase (OGG1) in mice. Somatic expansions exhibit tissue-specific differences and, in HD, occur predominantly in the brain (dotted oval). The absence of OGG1 significantly delays the age of disease onset in Hdh mice. This delayed onset of disease symptoms is recapitulated by inhibiting somatic expansion with a ROS scavenger, XJB-5-131. (B) Aberrant repair of DNA oxidative damage at (CAG)n repeats promotes somatic expansions. Initiation of 8-oxoguanine (8-oxoG) base excision repair by OGG1 leads to a nick in the damaged DNA strand. Subsequent strand-displacement synthesis by DNA polymerase β creates a 5ʹ-flap. A hairpin formed by CAG repeats in this flap could be stabilized by MutSβ and incorporated into the repaired DNA to generate an expansion. This expanded region is further subjected to ROS, possibly generating “toxic oxidation cycles” (dotted line).

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