Yang Chunxing, Qiao Tao, Yu Jia, Wang Hongyan, Guo Yansu, Salameh Johnny, Metterville Jake, Parsi Sepideh, Yusuf Issa, Brown Robert H, Cai Huaibin, Xu Zuoshang
Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
PLoS One. 2022 Feb 3;17(2):e0255710. doi: 10.1371/journal.pone.0255710. eCollection 2022.
Modestly increased expression of transactive response DNA binding protein (TDP-43) gene have been reported in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neuromuscular diseases. However, whether this modest elevation triggers neurodegeneration is not known. Although high levels of TDP-43 overexpression have been modeled in mice and shown to cause early death, models with low-level overexpression that mimic the human condition have not been established. In this study, transgenic mice overexpressing wild type TDP-43 at less than 60% above the endogenous CNS levels were constructed, and their phenotypes analyzed by a variety of techniques, including biochemical, molecular, histological, behavioral techniques and electromyography. The TDP-43 transgene was expressed in neurons, astrocytes, and oligodendrocytes in the cortex and predominantly in astrocytes and oligodendrocytes in the spinal cord. The mice developed a reproducible progressive weakness ending in paralysis in mid-life. Detailed analysis showed ~30% loss of large pyramidal neurons in the layer V motor cortex; in the spinal cord, severe demyelination was accompanied by oligodendrocyte injury, protein aggregation, astrogliosis and microgliosis, and elevation of neuroinflammation. Surprisingly, there was no loss of lower motor neurons in the lumbar spinal cord despite the complete paralysis of the hindlimbs. However, denervation was detected at the neuromuscular junction. These results demonstrate that low-level TDP-43 overexpression can cause diverse aspects of ALS, including late-onset and progressive motor dysfunction, neuroinflammation, and neurodegeneration. Our findings suggest that persistent modest elevations in TDP-43 expression can lead to ALS and other neurological disorders involving TDP-43 proteinopathy. Because of the predictable and progressive clinical paralytic phenotype, this transgenic mouse model will be useful in preclinical trial of therapeutics targeting neurological disorders associated with elevated levels of TDP-43.
在肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）及其他神经肌肉疾病中，已有报道称反式作用应答DNA结合蛋白（TDP - 43）基因表达有适度增加。然而，这种适度升高是否引发神经退行性变尚不清楚。尽管已在小鼠中构建了高水平TDP - 43过表达模型并显示会导致早期死亡，但尚未建立模拟人类情况的低水平过表达模型。在本研究中，构建了野生型TDP - 43过表达水平比内源性中枢神经系统水平高不到60%的转基因小鼠，并通过多种技术对其表型进行分析，包括生化、分子、组织学、行为学技术及肌电图检查。TDP - 43转基因在皮质的神经元、星形胶质细胞和少突胶质细胞中表达，在脊髓中主要在星形胶质细胞和少突胶质细胞中表达。这些小鼠出现了可重复的进行性肌无力，在中年时发展为瘫痪。详细分析显示，V层运动皮质中约30%的大锥体神经元丢失；在脊髓中，严重的脱髓鞘伴有少突胶质细胞损伤、蛋白质聚集、星形胶质细胞增生和小胶质细胞增生，以及神经炎症加剧。令人惊讶的是，尽管后肢完全瘫痪，但腰脊髓中的下运动神经元并未丢失。然而，在神经肌肉接头处检测到了失神经支配。这些结果表明，低水平TDP - 43过表达可导致ALS的多种表现，包括迟发性和进行性运动功能障碍、神经炎症和神经退行性变。我们的研究结果表明，TDP - 43表达持续适度升高可导致ALS及其他涉及TDP - 43蛋白病的神经疾病。由于具有可预测和进行性的临床麻痹表型，这种转基因小鼠模型将有助于针对与TDP - 43水平升高相关的神经疾病的治疗药物进行临床前试验。
