Age‐dependent and tissue‐specific CAG repeat instability occurs in mouse knock‐in for a mutant Huntington's disease gene

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by the expansion of CAG repeats in exon 1 of the HD gene. To clarify the instability of expanded CAG repeats in HD patients, an HD model mouse has been generated by gene replacement with human exon 1 of the HD gene with expansion to 77 CAG repeats. Chimeric proteins composed of human mutated exon 1 and mouse huntingtin are expressed ubiquitously in brain and peripheral tissues. One or two CAG repeat expansion was found in litters from paternal transmission, whereas contraction of CAG repeat in litters was observed through maternal transmission. Elderly mice show greater CAG repeat instability than younger mice, and a unique case was observed of an expanded 97 CAG repeat mouse. Somatic CAG repeat instability is particularly pronounced in the liver, kidney, stomach, and brain but not in the cerebellum of 100-week-old mice. The same results of expanded CAG repeat instability as observed in this HD model mouse were confirmed in the human brain of HD patients. Glial fibrillary acidic protein (GFAP)-positive cells have been found to be increased in the substantia nigra (SN), globus pallidus (GP), and striatum (St) in the brains of 40-week-old affected mice, although without neuronal cell death. The CAG repeat instability and increase in GFAP-positive cells in this mouse model appear to mirror the abnormalities in HD patients. The HD model mouse may therefore have advantages for investigations of molecular mechanisms underlying instability of CAG repeats.

Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products

“…8A). Our results are in accordance with those obtained in animal models of different polyQ diseases, in which age has been described as a CAG repeat instability modifier (Clark et al, 2007;Ishiguro et al, 2001;Sato et al, 1999). Interestingly, we also observed that different tissues exhibited different patterns of MI increase with age.…”

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…In humans, SCA1 is expressed throughout the brain, including non-neuronal cells. In a HD mouse model expressing 77 CAG repeats, glial fibrillary acidic protein (GFAP)-positive cells increase in the brains without any signs of neuronal degeneration (Ishiguro et al, 2001) and in genetically modified models of SCA7 it has been demonstrated that dysfunction of Bergmann glia leads to non-cell autonomous Purkinje cell degeneration in the absence of expression of mutant ataxin-7 in Purkinje cells. Moreover, GLASTdeficient mice fail motor challenging tasks and GLAST has active roles in synapse formation of cerebellar climbing fibre and in preventing excitotoxic cerebellar damage (Watase et al, 1998).…”

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

“…Small expansions upon paternal transmissions and CAG repeat contractions across maternal transmissions have been reported in about 20% of cases. As observed in HdhQ150, Hdh4/Q80 and Hdh6/Q72, HdhQ80 mice have shown somatic mosaicism that is age-dependent and biased toward expansions with the highest levels in the striatum and liver [35]. Compared to BACHD and knock-in mice described above, R6 and HdhQ111 mice are the most commonly used to identify the genetic modifiers of CAG repeat instability [24,32,45].…”

“…Therefore, mouse models have been generated to identify genetic modifiers of instability and to specify the mechanisms by which they act in HD. These mouse models including two HD transgenic mice with short gene fragment or BAC (R6 and BACHD), eight knock-in (the HdhQ20, HdhQ50, HdhQ92, HdhQ111, Hdh4/80, or Hdh6/72 lines, HdhQ150 and HdhQ80), have been created to analyze the dynamic of CAG repeat instability in germline and somatic tissues by different methods [24,[32][33][34][35][36] ( Table 1). The first method determines CAG repeat size by using unlabeled primers flanking CAG repeat.…”