Wang Wenzhang, Arakawa Hiroyuki, Wang Luwen, Okolo Ogoegbunam, Siedlak Sandra L, Jiang Yinfei, Gao Ju, Xie Fei, Petersen Robert B, Wang Xinglong
Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Rodent Behavioral Core, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Mol Ther. 2017 Jan 4;25(1):127-139. doi: 10.1016/j.ymthe.2016.10.013.
Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43 mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43 mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43 mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43 mice. Thus, this study suggests hemizygous TDP-43 mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.
TAR DNA结合蛋白43（TDP - 43）中的显性错义突变会导致肌萎缩侧索硬化症（ALS），TDP - 43在细胞质中的积累是ALS和额颞叶痴呆（FTD）的病理标志。表达致病人类TDP - 43 M337V突变体的转基因小鼠模型（TDP - 43小鼠）的行为学研究受到纯合转基因小鼠过早死亡以及据报道半合子转基因小鼠通过尾巴抬高和足迹评估缺乏表型的阻碍。在此，我们通过一系列运动协调和认知测试报告，8月龄的半合子TDP - 43小鼠存在明显的运动协调和认知缺陷。12月龄后，突变型TDP - 43的轻度表达会显著影响皮质神经元，其特征为细胞质TDP - 43定位错误、线粒体功能障碍和神经元丢失。与年龄匹配的非转基因小鼠相比，TDP - 43小鼠的总TDP - 43表达相似，但线粒体中的TDP - 43水平更高。有趣的是，一种TDP - 43线粒体定位抑制肽可消除细胞质中TDP - 43的积累，恢复线粒体功能，防止神经元丢失，并减轻成年半合子TDP - 43小鼠的运动协调和认知缺陷。因此，本研究表明半合子TDP - 43小鼠是研究TDP - 43毒性的有用动物模型，并进一步巩固了线粒体TDP - 43作为TDP - 43相关神经退行性疾病的新型治疗靶点。
