遺伝子ノックイン法により作製したハンチントン病 : モデルマウスの特徴

概要

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Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in exon 1 of the HD gene. Thus HD patients have the expanded polyglutamine tracts in the N-terminal fragment of huntingtin. To clarify the molecular mechanisms of the HD pathology, a knock-in mouse was generated by replacing exon 1 of the mouse HD gene with exon 1 containing expanded 77 CAG repeats of the human HD gene. Chimeric protein composed of human mutated exon 1 and mouse huntingtin were expressed in brain and peripheral tissues. Neuropathological features in elderly heterozygous knock-in mice, aggregates of N-terminal fragments of huntingtin were specifically formed in nuclei and neuropils in the striatal neurons, and in neuropils in their projection regions. These mutant mice demonstrated abnormal aggressive behavior. In elderly homozygous knock-in mice, heavy deposits of intranuclear and neuropil aggregates were detected, and characteristic large perikaryal aggregates were also found. However, cell death was not observed in these mutant mice. These huntingtin knock-in mice might be useful to provide an effective therapeutic approach against HD.