Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain

Abstract

Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

“…Striatum and cortex have shown a periodic expansion, whereas the other tissues reproduce a short continuous expansion overtime suggesting different mechanisms of instability in these tissues [51]. Large spontaneous expansions (>200 CAG) have been described in striatum and cortex from R6/2 mice [52] consistent with the observations done in brain from HD patients [25,43]. In R6/2 mice, the somatic mosaicism is correlated with the transmitted CAG repeat size but the somatic variation is not linear, particularly in striatum [52].…”

“…However, the mutation frequency is only 20% across generations compared to 70% in HD individuals [36]. Hdh4/Q80 and Hdh6/ Q72 have displayed somatic mosaicism that is tissue-specific, age-dependent and CAG repeat length dependent [25,36,42,43]. Some neurological and motor impairment have also been described in these mice and might be correlated to the somatic mosaicism level [25,36,44].…”

Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

“…Somatic repeat expansion in HD is shown to be more pronounced in the vulnerable cortical and striatal neurons in HD mice (Kennedy and Shelbourne, 2000;Ishiguro et al, 2001) and in HD patients (Shelbourne et al, 2007), and may be dependent on an agedependent oxidation-DNA damage repair cycle (Kovtun et al, 2007). Therefore, these results prompted the hypothesis that somatic repeat expansion in HD may be critical to disease onset and/or selective neuropathogenesis in the disorder (Kennedy and Shelbourne, 2000).…”

“…Somatic and germline repeat instability is present in multiple HD mouse models (Kennedy and Shelbourne, 2000;Ishiguro et al, 2001), and in postmortem HD brain tissues (Shelbourne et al, 2007). Somatic repeat expansion may be modified by the mismatch repair systems (Manley et al, 1999;Wheeler et al, 2003), and a recent study suggests it could be initiated by an age-dependent singlenucleotide excision DNA repair of oxidized nucleotides (Kovtun et al, 2007).…”

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

“…Long CAG repeat tracts in disease genes tend to be unstable in the germ line and in many somatic tissues, giving rise to contractions (fewer repeat units) and expansions (more repeat units), but usually with a distinct bias toward expansions. In the germ line, expansions lead to earlier disease onset and increased severity in affected individuals (40), while expansions in specific types of neuron may exacerbate the disease phenotype (13,40,49). Treatments designed to prevent repeat expansion or to promote repeat contraction would be welcome, but no such treatments exist, and their development will depend on a better understanding of the mechanisms responsible for repeat instability (34).…”