Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease?

Abstract

An unstable CAG triplet repeat expansion encoding a polyglutamine stretch within the ubiquitously expressed protein huntingtin is responsible for causing Huntington's disease (HD). By quantifying the repeat sizes of individual mutant alleles in tissues derived from an accurate genetic mouse model of HD we show that the mutation becomes very unstable in striatal tissue. The expansion-biased changes increase with age, such that some striatal cells from old HD mice contain mutations that have tripled in size. If this pattern of repeat instability is recapitulated in human striatal tissue, the concomitant increased polyglutamine load may contribute to the patterns of selective neuronal cell death in HD. Our findings also suggest that trinucleotide repeat instability can occur by mechanisms that are not replication-based.

Mouse models of Huntington's disease

“…First, routine measurement of CAG-CAA tract size in each BAC HD and YAC128 animal used for breeding and/ or experimentation is not necessary as the tract sizes are highly stable in the germ line (Gray et al, 2008;Slow et al, 2003). Second, while this stability is convenient in terms of maintaining and breeding these mice for experimentation, questions remain regarding the result of such CAG-CAA sequences on HD pathophysiology in the mouse, especially in the context of the potential role of RNA structure and toxicity (Banez-Coronel et al, 2012) and the importance of somatic instability (Kennedy and Shelbourne, 2000;Swami et al, 2009) in eliciting such pathophysiology. Essentially, the BAC HD mice and to some extent the YAC128 mice do not exactly model the HD mutation at the DNA sequence level and care should be taken in using these models where RNA structure and somatic instability mechanisms are under investigation.…”

“…It should be noted that all of the HD knock-in mice that carry pure CAG expansions in exon 1 are subject to germ line and somatic CAG repeat instability (Hunter et al, 2005;Kennedy and Shelbourne, 2000;Lee et al, 2011). In fact, this phenomenon was used by the Detloff group to generate sublines of their knock-in mice that have differing CAG repeat numbers.…”

“…As mentioned above, however, many of the N-terminal transgenic and knock-in models demonstrate both germ line and somatic instability (Gonitel et al, 2008;Kennedy and Shelbourne, 2000;Lee et al, 2011;Mangiarini et al, 1997;Wheeler et al, 1999), meaning that continuous monitoring of animal models containing CAG repeats is essential for preserving the phenotypic characteristics of the strain caused by the repeat expansion. Similar to human observations, increases of CAG repeat lengths in progeny has been observed in colonies commonly maintained through the male line (Figure 1).…”

Slipping while sleeping? Trinucleotide repeat expansions in germ cells

“…Notably, tissue-specific somatic instability in HD and other diseases (Figure 1a) might occur by processes that are unrelated to germ cells [23,26,27]. In DM1 and SCA8, which, like HD, are caused by an unstable CTG or CAG repeat, families show a maternal bias rather than a paternal bias for large expansions.…”

“…Incidentally, somatic CAG instability in the brains of HD patients might not occur by the assumed process of genome maintenance repair [27], as recent evidence has revealed increased cell proliferation and neurogenesis in HD brains [32]. Also, spontaneous locus-0specific CTG expansions in cultured DM1 patient fibroblasts occurred only during proliferation, and these were specifically enhanced by chemicals that perturb replication-fork progression [31].…”