Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
J Biol Chem. 2010 Apr 9;285(15):11068-72. doi: 10.1074/jbc.C109.078527. Epub 2010 Feb 12.
TDP-43 (43-kDa TAR DNA-binding protein) is a major constituent of ubiquitin-positive cytosolic aggregates present in neurons of patients with amyotrophic lateral sclerosis (ALS) and ubiquitin-positive fronto-temporal lobar degeneration (FTLD-U). Inherited mutations in TDP-43 have been linked to familial forms of ALS, indicating a key role for TDP-43 in disease pathogenesis. Here, we describe a Drosophila melanogaster model of TDP-43 proteinopathy. Expression of wild-type human TDP-43 protein in Drosophila motor neurons led to motor dysfunction and dramatic reduction of life span. Interestingly, coexpression of ubiquilin 1, a previously identified TDP-43-interacting protein with suspected functions in autophagy and proteasome targeting, reduced steady-state TDP-43 expression but enhanced the severity of TDP-43 phenotypes. Finally, ectopically expressed TDP-43 was largely localized to motor neuron nuclei, suggesting that expression of wild-type TDP-43 alone is detrimental even in the absence of cytosolic aggregation. Our findings demonstrate that TDP-43 exerts cell-autonomous neurotoxicity in Drosophila and further imply that dose-dependent alterations of TDP-43 nuclear function may underlie motor neuron death in ALS.
TDP-43（43kDa TAR DNA 结合蛋白）是肌萎缩侧索硬化症（ALS）患者神经元中存在的泛素阳性细胞浆聚集物和泛素阳性额颞叶变性（FTLD-U）的主要成分。TDP-43 的遗传突变与家族性 ALS 有关，表明 TDP-43 在疾病发病机制中起关键作用。在这里，我们描述了一个 TDP-43 蛋白病的果蝇模型。野生型人 TDP-43 蛋白在果蝇运动神经元中的表达导致运动功能障碍和寿命的显著缩短。有趣的是，泛素结合蛋白 1 的共表达，一种先前被鉴定的与自噬和蛋白酶体靶向有关的 TDP-43 相互作用蛋白，降低了 TDP-43 的稳态表达，但增强了 TDP-43 表型的严重程度。最后，异位表达的 TDP-43 主要定位于运动神经元核，这表明即使在没有细胞浆聚集的情况下，野生型 TDP-43 的表达本身也是有害的。我们的发现表明，TDP-43 在果蝇中发挥细胞自主神经毒性作用，并进一步表明 TDP-43 核功能的剂量依赖性改变可能是 ALS 中运动神经元死亡的基础。
