Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes

Ella Dragileva, Audrey Hendricks, Allison Teed, Tammy Gillis, Edith T. Lopez, Errol C. Friedberg, Raju Kucherlapati, Winfried Edelmann, Kathryn L. Lunetta, Marcy E. MacDonald, Vanessa C. Wheeler

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Modifying the length of the Huntington's disease (HD) CAG repeat, the major determinant of age of disease onset, is an attractive therapeutic approach. To explore this we are investigating mechanisms of intergenerational and somatic HD CAG repeat instability. Here, we have crossed HD CAG knock-in mice onto backgrounds deficient in mismatch repair genes, Msh3 and Msh6, to discern the effects on CAG repeat size and disease pathogenesis. We find that different mechanisms predominate in inherited and somatic instability, with Msh6 protecting against intergenerational contractions and Msh3 required both for increasing CAG length and for enhancing an early disease phenotype in striatum. Therefore, attempts to decrease inherited repeat size may entail a full understanding of Msh6 complexes, while attempts to block the age-dependent increases in CAG size in striatal neurons and to slow the disease process will require a full elucidation of Msh3 complexes and their function in CAG repeat instability.

Original languageEnglish (US)
Pages (from-to)37-47
Number of pages11
JournalNeurobiology of Disease
Volume33
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

Corpus Striatum
Huntington Disease
DNA Repair
Genes
DNA Mismatch Repair
Age of Onset
Phenotype
Neurons
Therapeutics

Keywords

  • Huntington's disease
  • Instability
  • Knock-in
  • Mouse
  • Pathogenesis
  • Repair
  • Repeat
  • Striatum
  • Trinucleotide

ASJC Scopus subject areas

  • Neurology

Cite this

Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. / Dragileva, Ella; Hendricks, Audrey; Teed, Allison; Gillis, Tammy; Lopez, Edith T.; Friedberg, Errol C.; Kucherlapati, Raju; Edelmann, Winfried; Lunetta, Kathryn L.; MacDonald, Marcy E.; Wheeler, Vanessa C.

In: Neurobiology of Disease, Vol. 33, No. 1, 01.2009, p. 37-47.

Research output: Contribution to journalArticle

Dragileva, E, Hendricks, A, Teed, A, Gillis, T, Lopez, ET, Friedberg, EC, Kucherlapati, R, Edelmann, W, Lunetta, KL, MacDonald, ME & Wheeler, VC 2009, 'Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes', Neurobiology of Disease, vol. 33, no. 1, pp. 37-47. https://doi.org/10.1016/j.nbd.2008.09.014
Dragileva, Ella ; Hendricks, Audrey ; Teed, Allison ; Gillis, Tammy ; Lopez, Edith T. ; Friedberg, Errol C. ; Kucherlapati, Raju ; Edelmann, Winfried ; Lunetta, Kathryn L. ; MacDonald, Marcy E. ; Wheeler, Vanessa C. / Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. In: Neurobiology of Disease. 2009 ; Vol. 33, No. 1. pp. 37-47.
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