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

Abstract

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.

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

“…A number of enzymes with the ability to nick DNA and therefore necessitate DNA repair are known to promote CAG expansion and both somatic expansion and HD‐related phenotypes are ameliorated in mouse models by manipulating genes associated with DNA repair 15, 29, 30, 31, 32. Critically, delay in phenotype onset in HD mice was recently demonstrated through suppressing somatic expansion by crossing HTT knock in mice with Ogg1 –/– mice, lacking the DNA cleaving 7,8‐dihydro‐8‐oxo‐guanine (8‐oxo‐G) glycosylase 16. Notably, the single most significant SNP in the present study, rs3512, is in the 3′UTR of FAN1 , which has DNA endo/exonuclease activity.…”

“…It occurs in postmitotic neurons and is prominent in striatum and cortex, tissues particularly affected in HD 13. Somatic instability has been linked to disease onset and progression in both human14 and mouse HD studies,15 and decreasing somatic expansion in HD model mice delays phenotype progression 16. Many of the principles of somatic instability in HD extend to SCAs 1, 10.…”

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

“…Our data caution that inducing DSBs within the repeat tract in an attempt to shrink them would also lead to repeat expansion. This would be a problem because the expansions are likely to exacerbate the disease phenotype2223. An alternative may be to induce two DSBs in regions immediately flanking, but not within, the repeat tract.…”

“…It has therefore been proposed that contracting the repeat tract would be beneficial in reducing phenotype expression. Repeat expansion, on the other hand, would further exacerbate the disease symptoms42223. Currently, there is no treatment that specifically shrinks CAG repeats.…”

The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington’s disease

“…Blocking somatic expansion in mice suppresses pathophysiology (Budworth et al, 2015; Budworth and McMurray, 2016), indicating that somatic changes in repeat tract number during life contribute to toxicity in addition to the inherited expanded allele. The regional variability in energy deficits may reflect, at least in part, the individual cell variations in the CAG tract length among brain regions (Budworth et al, 2015; Budworth and McMurray, 2016; Swami et al, 2009; Kennedy et al, 2003; Kennedy and Shelbourne, 2000). Thus, multiple contributions have an influence on neuronal survival, which affects the heterogeneous composition of cell types and complicates an already complicated bioenergetic explanation of toxicity at late stages of the disease.…”