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, 11 (8), e1005267

Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease


Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease

Helen Budworth et al. PLoS Genet.


Huntington's Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.

Conflict of interest statement

The authors have declared that no competing interests exist.


Fig 1
Fig 1. Hdh(Q150/Q150)/ogg1(+/+) and Hdh(Q150/Q150)/ogg1(-/-) animals are similar by physiological criteria.
(A) Schematic of crosses between Hdh(Q150/wt) and ogg1(+/-); (*) only a subset of the resulting genotypes from the breeding step are shown. The OGG1 (B) The average litter size for Hdh(Q150/Q150)ogg1(+/+), Hdh(Q150/Q150)ogg1(-/-), Hdh(wt/wt)/ogg1(-/-) and Hdh(wt/wt)/ogg1(+/+) genotypes. (C) The average weight (grams) for Hdh(Q150/Q150)ogg1(+/+), Hdh(Q150/Q150)ogg1(-/-), Hdh(wt/wt)/ogg1(-/-) and Hdh(wt/wt)/ogg1(+/+) animals at 25 weeks. A full table of weights and litter sizes for all nine genotypes are presented in S1 Table (in S2B Fig). (D) OGG1 resolved on an SDS-PAGE gel migrates as a 41 kDa (368 aa) protein. The age-dependence of OGG1 protein expression relative to actin controls: Y is 7–10 weeks, M is 12–16 weeks; O is greater than 30 weeks. The brain regions are; STR is striatum, CBL is cerebellum, HIP is hippocampus, CTX is cortex, as indicated. (E) Histological analysis of brain slices (caudate-putamen) from Hdh(Q150/Q150)ogg1(+/+), Hdh(Q150/Q150)ogg1(-/-), and Hdh(wt/wt)/ogg1(-/-) at 7–16 weeks. H&E is Hematoxylin and Eosin, which visualize protein and nucleic acid-rich regions, NeuN detects neurons, IBA1 is ionized calcium binding adaptor molecule 1, which detects microgliosis, and LN (Luxol-Nissl) stain detects overall cellular pattern and morphology. Scale bar is 50μm. Quantification of neurons by NeuN staining comprised 3 animals, 5–10 tissues slices and 10 random fields on each slice. (F) Quantification of the number of NeuN positive cells from digital images of brain slices of each of the three indicated genotypes. Shown are the histological analysis for only three genotypes that are most likely to exhibit pathophysiology. None of the genotypes displayed differences relative to controls.
Fig 2
Fig 2. Loss of OGG1 suppresses the average repeat length in Hdh(Q150/Q150)/ogg1(-/-) animals.
(A) Schematic representation of the experiment, as described in text. The red lines depict the Hdh alleles in a heterozygous Hdh animals that do Hdh(Q150/Q150)/ogg1(+/+) or do not (Q150/wt)/ogg1(-/-) express OGG1. The blue lines depict the ogg1 alleles and no blue lines indicate their absence in Hdh(Q150/wt)/ogg1(-/-) mice. The absence of OGG1 in the Hdh(Q150/wt)/ogg1(-/-) suppresses age-dependent somatic expansion (+CAG) that is observed in the Hdh(Q150) allele of Hdh(Q150/wt)/ogg1(+/+) animals. The increased length of the red line represents somatic expansion the long, disease-length allele. (B) The stacked bar graph is a frequency plot for pooled normalized repeat tracts from a representative set of animals for illustration purposes (n = 6) (B) Hdh(Q150/Q150)/ogg1(+/+) and (C) Hdh(Q150/Q150)/ogg1(-/-) animals in the striatum at 10 weeks to demonstrate the asymmetry of the distributions, as indicated. Colors represent individual mice. CAG repeats at HD locus were amplified and analyzed as described previously [19]. Data were analyzed using GeneMapper software v4.
Fig 3
Fig 3. The distribution of CAG tract suppression by OGG1 is region-specific and affects tract sizes across the entire asymmetric distribution.
(A) Analyzed were the pooled distributions from the entire set of somatic changes in each of the Hdh(Q150/Q150)/ogg1(+/+) and Hdh(Q150/Q150)/ogg1(-/-) animals between birth and 40 weeks (N = 160–200 per genotype). Each cell is the difference in size between the Hdh(Q150/Q150)/ogg1(+/+) and Hdh(Q150/Q150)/ogg1(-/-) genotypes in the segmented quantiles, from 1 to 99. The differences along the asymmetric distributions indicate the sizes of the somatic expansions that were suppressed by OGG1 in each of the indicated brain regions. The changes in CAG tract length were not statistically different in animals that harbored one or two Hdh(Q150) alleles and so they were pooled in each distribution to increase the power of the analyses. Bracketed lines represent 1 SE. Significance levels coded: * P≤0.05; † P≤0.01; ‡ P≤0.005. (B) Examples of pooled distributions in striatum over 40 weeks, illustrating the altered CAG repeat tract lengths.
Fig 4
Fig 4. Suppression of somatic expansion delays motor decline in animals with similar inherited repeats.
(A) The trends of motor decline versus genotype, as judged by linear fits of the averages. Motor performance in animals is affected by the mHTT and OGG1 genotype in an opposite manner. (top panel) Motor decline depends on the complement of mHTT in the presence of OGG1. (middle panel) Loss of two OGG1 alleles suppresses the average motor decline in Hdh(Q150/150)/ogg1(-/-) animals that express only one mHTT allele. (lower panel) Direct comparison of the motor decline in Hdh(Q150/150)/ogg1(+/+) and Hdh(Q150/150)/ogg1(-/-) littermates. Points are plotted mid-range of the age group, ie. 15 weeks is representative of the whole 11–20 week age group. (B) Box and whisker plots for rotarod performance (time on the rod) versus Hdh and ogg1 genotypes. The thin vertical lines (whiskers) represent the entire distribution of performances at the indicated ages (see S6B Fig). Boxes represent the median 50% of performance values, with 25% above the median and 25% below the median. The horizontal line in the box indicates the median. The dotted horizontal line across the plot in each age group is the global average of performances when all 6 genotypes are combined. N = 16–20 animals per age group per genotype. Motor function was measured using a rotarod apparatus with a fixed-speed protocol described previously [36, 49, 50].
Fig 5
Fig 5. Pharmacological intervention suppresses oxidative DNA damage and somatic mutation in vivo.
XJB-5-131 synthesis [51] and administration is as previously described [36]. (A) OGG1 and XJB-5-131 act in the same expansion pathway. Schematic diagram for the mechanism of somatic expansion (adapted from [1]), and the point of inhibition by XJB-5-131 or loss of OGG1. XJB-5-131 reduces oxidative DNA damage (the substrate for OGG1) and loss of OGG1 reduces base excision and single strand break intermediates for expansion by BER. (B) Representative examples of GeneScan analysis of Hdh(Q150/Q150)/ogg1(+/+) striatum of animals untreated or treated with XJB-5-131. (C) Quantification of repeat changes ± standard deviation for animals age 21–30 weeks. The somatic expansions in XJB-5-131-treated Hdh(Q150/Q150)/ogg1(+/+) animals are smaller than in untreated animals in the striatum. N = 6 per group (with and without XJB-5-131 treatment) *p<0.001. (D) Levels of mtDNA abundance in cerebral cortex of Hdh(wt/wt), Hdh(Q150/Q150)/ogg1(+/+) and Hdh(Q150/Q150)/ogg1(-/-) animals at 12–16 weeks (n = 6) and >80 weeks of age (n = 6–9). §p<0.0001 versus 12–16 weeks WT and p<0.0001 versus >80 weeks WT.
Fig 6
Fig 6. Model for somatic expansion and the age of disease onset.
(A) In a conventional model, expansion arises from decades long toxic effects of expanded protein or RNA. Intervention is limited to breaking mHTT interactions with cellular proteins, which has not yet been therapeutically effective. In a somatic threshold model, toxicity arises when an inherited allele reaches a somatic length that is sufficient to support sustained toxicity. (B) We propose a two-state model for toxicity. The inherited repeats govern “if” disease will arise, while the somatic expansion governs, at least in part, the “when”. Intervention is possible by blocking the somatic expansion and delaying onset of disease.

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