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

Overview

Journal PLoS Genet

Specialty Genetics

Date 2015 Aug 7

PMID 26247199

Citations 52

Authors

Helen Budworth

Faye R Harris

Paul Williams

Do Yup Lee

Amy Holt

Jens Pahnke

Bartosz Szczesny

Karina Acevedo-Torres

Sylvette Ayala-Pena

Cynthia T McMurray

Affiliations

Soon will be listed here.

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.

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References

Trushina E, Canaria C, Lee D, McMurray C . Loss of caveolin-1 expression in knock-in mouse model of Huntington's disease suppresses pathophysiology in vivo. Hum Mol Genet. 2013; 23(1):129-44. PMC: 3857950. DOI: 10.1093/hmg/ddt406. View

Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates G . Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat Genet. 1997; 15(2):197-200. DOI: 10.1038/ng0297-197. View

Arai T, Kelly V, Minowa O, Noda T, Nishimura S . The study using wild-type and Ogg1 knockout mice exposed to potassium bromate shows no tumor induction despite an extensive accumulation of 8-hydroxyguanine in kidney DNA. Toxicology. 2006; 221(2-3):179-86. DOI: 10.1016/j.tox.2006.01.004. View

Kennedy L, Evans E, Chen C, Craven L, Detloff P, Ennis M . Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet. 2003; 12(24):3359-67. DOI: 10.1093/hmg/ddg352. View

Kovalenko M, Dragileva E, St Claire J, Gillis T, Guide J, New J . Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice. PLoS One. 2012; 7(9):e44273. PMC: 3436885. DOI: 10.1371/journal.pone.0044273. View

Aronin N, Chase K, Young C, Sapp E, Schwarz C, Matta N . CAG expansion affects the expression of mutant Huntingtin in the Huntington's disease brain. Neuron. 1995; 15(5):1193-201. DOI: 10.1016/0896-6273(95)90106-x. View

Andresen J, Gayan J, Djousse L, Roberts S, Brocklebank D, Cherny S . The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset. Ann Hum Genet. 2006; 71(Pt 3):295-301. DOI: 10.1111/j.1469-1809.2006.00335.x. View

Johri A, Calingasan N, Hennessey T, Sharma A, Yang L, Wille E . Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Hum Mol Genet. 2011; 21(5):1124-37. PMC: 3277311. DOI: 10.1093/hmg/ddr541. View

Hubert Jr L, Lin Y, Dion V, Wilson J . Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum Mol Genet. 2011; 20(24):4822-30. PMC: 3221534. DOI: 10.1093/hmg/ddr421. View

10.

Gayan J, Brocklebank D, Andresen J, Alkorta-Aranburu G, Cader M, Roberts S . Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds. Genet Epidemiol. 2008; 32(5):445-53. DOI: 10.1002/gepi.20317. View

11.

Dragileva E, Hendricks A, Teed A, Gillis T, Lopez E, Friedberg E . Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. Neurobiol Dis. 2008; 33(1):37-47. PMC: 2811282. DOI: 10.1016/j.nbd.2008.09.014. View

12.

Lin C, Chien W, Cearley J, JACKSON W, Crouse A, Ren S . Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum Mol Genet. 2001; 10(2):137-44. DOI: 10.1093/hmg/10.2.137. View

13.

Giovannone B, Sabbadini G, Di Maio L, Calabrese O, Castaldo I, Frontali M . Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from intermediate and expanded Huntington disease gene carriers. Hum Mutat. 1997; 10(6):458-64. DOI: 10.1002/(SICI)1098-1004(1997)10:6<458::AID-HUMU7>3.0.CO;2-9. View

14.

Djousse L, Knowlton B, Hayden M, Almqvist E, Brinkman R, Ross C . Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics. 2004; 5(2):109-14. PMC: 1866166. DOI: 10.1007/s10048-004-0175-2. View

15.

Bak S, Sakellariou D, Pena-Diaz J . The dual nature of mismatch repair as antimutator and mutator: for better or for worse. Front Genet. 2014; 5:287. PMC: 4139959. DOI: 10.3389/fgene.2014.00287. View

16.

Ishiguro H, Yamada K, Sawada H, Nishii K, Ichino N, Sawada M . Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene. J Neurosci Res. 2001; 65(4):289-97. DOI: 10.1002/jnr.1153. View

17.

van den Broek W, Nelen M, Wansink D, Coerwinkel M, Te Riele H, Groenen P . Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Hum Mol Genet. 2002; 11(2):191-8. DOI: 10.1093/hmg/11.2.191. View

18.

Wipf P, Xiao J, Jiang J, Belikova N, Tyurin V, Fink M . Mitochondrial targeting of selective electron scavengers: synthesis and biological analysis of hemigramicidin-TEMPO conjugates. J Am Chem Soc. 2005; 127(36):12460-1. DOI: 10.1021/ja053679l. View

19.

Andrew S, Goldberg Y, Kremer B, Telenius H, Theilmann J, Adam S . The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993; 4(4):398-403. DOI: 10.1038/ng0893-398. View

20.

Kovtun I, Liu Y, Bjoras M, Klungland A, Wilson S, McMurray C . OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature. 2007; 447(7143):447-52. PMC: 2681094. DOI: 10.1038/nature05778. View