Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
Hum Mol Genet. 2011 May 15;20(10):1952-65. doi: 10.1093/hmg/ddr076. Epub 2011 Feb 25.
TAR DNA-binding protein 43 (TDP-43) plays a key role in the neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The nature of the TDP-43-mediated neurotoxicity associated with these diseases is not yet understood. Here, we have established transgenic Caenorhabditis elegans models that express human TDP-43 variants in the nervous system, including the full-length wild-type (WT) and mutant proteins and a pathologic C-terminal fragment. The C. elegans models developed severe locomotor defects associated with the aggregation of TDP-43 in neurons. In comparison to parallel Cu/Zn superoxide dismutase worm models, transgenic full-length TDP-43, including the WT protein, was highly neurotoxic. In addition, TDP-43 demonstrated an unusually high tendency to aggregate, a property intrinsic to the WT protein. The C-terminal 25 kDa fragment of TDP-43 was unstable but remarkably aggregation-prone. Distinct disulfide-linked TDP-43 dimers and oligomers were detected. In C. elegans, the neurotoxicity and the protein aggregation of TDP-43 were regulated by environmental temperature and heat shock transcriptional factor 1, indicating that a deficiency in protein quality control is a risk factor for TDP-43 proteinopathy. Furthermore, the neurotoxicity and the protein aggregation of TDP-43 can be significantly attenuated by a deficiency in the insulin/insulin-like growth factor 1 (IGF-1) signaling in C. elegans and mammalian cells. These results suggest that protein misfolding underlies the aging-dependent neurodegeneration associated with TDP-43 and that the insulin/IGF-1 signaling may be a target for therapies.
TAR DNA 结合蛋白 43（TDP-43）在包括肌萎缩性侧索硬化症和额颞叶变性在内的神经退行性疾病中发挥关键作用。与这些疾病相关的 TDP-43 介导的神经毒性的性质尚不清楚。在这里，我们建立了转基因秀丽隐杆线虫模型，这些模型在神经系统中表达人类 TDP-43 变体，包括全长野生型（WT）和突变蛋白以及病理性 C 端片段。开发的秀丽隐杆线虫模型表现出严重的运动缺陷，与神经元中 TDP-43 的聚集有关。与平行的 Cu/Zn 超氧化物歧化酶线虫模型相比，转基因全长 TDP-43，包括 WT 蛋白，具有高度神经毒性。此外，TDP-43 表现出异常高的聚集倾向，这是 WT 蛋白的固有特性。TDP-43 的 C 端 25 kDa 片段不稳定，但极易聚集。检测到不同的二硫键连接的 TDP-43 二聚体和寡聚体。在秀丽隐杆线虫中，TDP-43 的神经毒性和蛋白质聚集受环境温度和热休克转录因子 1 的调节，表明蛋白质质量控制的缺陷是 TDP-43 蛋白病的一个风险因素。此外，在秀丽隐杆线虫和哺乳动物细胞中，胰岛素/胰岛素样生长因子 1（IGF-1）信号的缺乏可以显著减轻 TDP-43 的神经毒性和蛋白质聚集。这些结果表明，蛋白质错误折叠是与 TDP-43 相关的衰老依赖性神经退行性变的基础，胰岛素/IGF-1 信号可能是治疗的靶点。
