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

Hiroshi Ishiguro, Koji Yamada, Hirohide Sawada, Kazuhiro Nishii, Naohiro Ichino, Makoto Sawada, Yoshikazu Kurosawa, Natsuki Matsushita, Kazuto Kobayashi, Jun Goto, Hideji Hashida, Naoki Masuda, Ichiro Kanazawa, Toshiharu Nagatsu

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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.

Original languageEnglish
Pages (from-to)289-297
Number of pages9
JournalJournal of Neuroscience Research
Issue number4
Publication statusPublished - 15-08-2001


All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cite this

Ishiguro, H., Yamada, K., Sawada, H., Nishii, K., Ichino, N., Sawada, M., Kurosawa, Y., Matsushita, N., Kobayashi, K., Goto, J., Hashida, H., Masuda, N., Kanazawa, I., & Nagatsu, T. (2001). Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene. Journal of Neuroscience Research, 65(4), 289-297.