title: Continuous and periodic expansion of CAG repeats in Huntington's disease R6/1 mice.
abstract: Huntington's disease (HD) is one of several neurodegenerative disorders caused by expansion of CAG repeats in a coding gene. Somatic CAG expansion rates in HD vary between organs, and the greatest instability is observed in the brain, correlating with neuropathology. The fundamental mechanisms of somatic CAG repeat instability are poorly understood, but locally formed secondary DNA structures generated during replication and/or repair are believed to underlie triplet repeat expansion. Recent studies in HD mice have demonstrated that mismatch repair (MMR) and base excision repair (BER) proteins are expansion inducing components in brain tissues. This study was designed to simultaneously investigate the rates and modes of expansion in different tissues of HD R6/1 mice in order to further understand the expansion mechanisms in vivo. We demonstrate continuous small expansions in most somatic tissues (exemplified by tail), which bear the signature of many short, probably single-repeat expansions and contractions occurring over time. In contrast, striatum and cortex display a dramatic--and apparently irreversible--periodic expansion. Expansion profiles displaying this kind of periodicity in the expansion process have not previously been reported. These in vivo findings imply that mechanistically distinct expansion processes occur in different tissues.
authors.affiliation: Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Oslo University Hospital, Oslo, Norway.
authors.forename: Linda
authors.initials: L
authors.lastname: Møllersen
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Rowe
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Larsen
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Rognes
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins