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

Budworth, Helen; Harris, Frances; Williams, Paul D.; Lee, Mi Kyung; Holt, Amy; Pahnke, Jens; Szczesny, Bartosz; Acevedo‐Torres, Karina; Ayala‐Peña, Sylvette; McMurray, Cynthia T.

doi:10.1371/journal.pgen.1005267

Cited by 73 publications

(90 citation statements)

References 49 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

et al. 2016

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CAG/CTG repeat expansions cause over 13 neurological diseases that remain without a cure. Because longer tracts cause more severe phenotypes, contracting them may provide a therapeutic avenue. No currently known agent can specifically generate contractions. Using a GFP-based chromosomal reporter that monitors expansions and contractions in the same cell population, here we find that inducing double-strand breaks within the repeat tract causes instability in both directions. In contrast, the CRISPR-Cas9 D10A nickase induces mainly contractions independently of single-strand break repair. Nickase-induced contractions depend on the DNA damage response kinase ATM, whereas ATR inhibition increases both expansions and contractions in a MSH2- and XPA-dependent manner. We propose that DNA gaps lead to contractions and that the type of DNA damage present within the repeat tract dictates the levels and the direction of CAG repeat instability. Our study paves the way towards deliberate induction of CAG/CTG repeat contractions in vivo.

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Section: Discussionmentioning

confidence: 99%

“…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.…”

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Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

et al. 2016

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

197

186

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ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

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“…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.…”

Section: Defects In Oxidative Phosphorylation In Human Brainmentioning

confidence: 99%

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

Polyzos

McMurray

2017

Mechanisms of Ageing and Development

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Mitochondrial dysfunction and ensuing oxidative damage is typically thought to be a primary cause of Huntington’s disease, Alzheimer’s disease and Parkinson disease. There is little doubt that mitochondria (MT) become defective as neurons die, yet whether MT defects are the primary cause or a detrimental consequence of toxicity remains unanswered. Oxygen consumption rate (OCR) and glycolysis provide sensitive and informative measures of the functional status MT and the cells metabolic regulation, yet these measures differ depending on the sample source; species, tissue type, age at measurement, and whether MT are measured in purified form or in a cell. The effects of these various parameters are difficult to quantify and not fully understood, but clearly have an impact on interpreting the bioenergetics of MT or their failure in disease states. A major goal of the review is to discuss issues and coalesce detailed information into a reference table to help in assessing mitochondrial dysfunction as a cause or consequence of Huntington’s disease.

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

Cited by 73 publications

References 49 publications

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

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

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

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