von Hörsten Stephan, Schmitt Ina, Nguyen Huu Phuc, Holzmann Carsten, Schmidt Thorsten, Walther Thomas, Bader Michael, Pabst Reinhard, Kobbe Philipp, Krotova Jana, Stiller Detlef, Kask Ants, Vaarmann Annika, Rathke-Hartlieb Silvia, Schulz Jörg B, Grasshoff Ute, Bauer Ingrid, Vieira-Saecker Ana Maria Menezes, Paul Martin, Jones Lesley, Lindenberg Katrin S, Landwehrmeyer Bernhard, Bauer Andreas, Li Xiao-Jiang, Riess Olaf
Department of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
Hum Mol Genet. 2003 Mar 15;12(6):617-24. doi: 10.1093/hmg/ddg075.
Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.
亨廷顿舞蹈症（HD）是一种在人类中表现较晚的神经退行性疾病，由一个功能未知基因中CAG三核苷酸重复序列扩展至39个以上单位所致。已报道了几种小鼠模型，其中一些（转基因模型）表现出快速的表型进展，在3至5个月内导致死亡，类似于罕见的青少年型HD（韦斯特法尔变异型），而另一些（敲入小鼠）则没有任何症状。由于小鼠脑体积小，不适合进行重复性的体内成像研究。此外，转基因模型中疾病的快速进展限制了它们在神经移植方面的应用。因此，我们构建了一种HD转基因大鼠模型，其携带一个截短的亨廷顿蛋白cDNA片段，带有51个CAG重复序列，受大鼠天然亨廷顿蛋白启动子的控制。这是首个脑部神经退行性疾病的转基因大鼠模型。这些大鼠表现出成年期发病的神经学表型，包括焦虑减轻、认知障碍、缓慢进展的运动功能障碍，以及脑部神经元核内包涵体形式的典型组织病理学改变。与HD患者一样，体内成像显示磁共振图像上纹状体萎缩，在高分辨率氟脱氧葡萄糖正电子发射断层扫描研究中脑葡萄糖代谢降低。该模型允许进行纵向体内成像研究，因此非常适合评估神经移植等新型治疗方法。
