Yu-Taeger Libo, Gaiser Viktoria, Lotzer Larissa, Roenisch Tina, Fabry Benedikt Timo, Stricker-Shaver Janice, Casadei Nicolas, Walter Michael, Schaller Martin, Riess Olaf, Nguyen Huu Phuc, Ott Thomas, Grundmann-Hauser Kathrin
Institute for Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany.
Centre for Rare Diseases, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany.
Biol Open. 2018 Jul 23;7(7):bio032839. doi: 10.1242/bio.032839.
A three-base-pair deletion in the human gene is causative for the most common form of primary dystonia: the early-onset dystonia type 1 (DYT1 dystonia). The pathophysiological consequences of this mutation are still unknown. To study the pathology of the mutant torsinA (TOR1A) protein, we have generated a transgenic rat line that overexpresses the human mutant protein under the control of the human promoter. This new animal model was phenotyped with several approaches, including behavioral tests and neuropathological analyses. Motor phenotype, cellular and ultrastructural key features of torsinA pathology were found in this new transgenic rat line, supporting that it can be used as a model system for investigating the disease's development. Analyses of mutant TOR1A protein expression in various brain regions also showed a dynamic expression pattern and a reversible nuclear envelope pathology. These findings suggest the differential vulnerabilities of distinct neuronal subpopulations. Furthermore, the reversibility of the nuclear envelope pathology might be a therapeutic target to treat the disease.
人类基因中的一个三碱基对缺失是最常见的原发性肌张力障碍形式——早发性肌张力障碍1型（DYT1肌张力障碍）的病因。这种突变的病理生理后果仍然未知。为了研究突变型扭转蛋白A（TOR1A）蛋白的病理学，我们构建了一个转基因大鼠品系，该品系在人类启动子的控制下过表达人类突变蛋白。我们采用了多种方法对这个新的动物模型进行表型分析，包括行为测试和神经病理学分析。在这个新的转基因大鼠品系中发现了TOR1A病理的运动表型、细胞和超微结构关键特征，这支持它可以作为研究该疾病发展的模型系统。对不同脑区突变型TOR1A蛋白表达的分析还显示出动态表达模式和可逆的核膜病理。这些发现提示了不同神经元亚群的不同易损性。此外，核膜病理的可逆性可能是治疗该疾病的一个治疗靶点。
