Rapamycin alleviates pathogenesis of a new Drosophila model of ALS-TDP
Rapamycin alleviates pathogenesis of a new Drosophila model of ALS-TDP
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DOI：
10.3109/01677063.2015.1077832
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发表时间：
2015-01-01
影响因子：
1.9
通讯作者：
Shen, Che-Kun James
中科院分区：
文献类型：
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作者：
Cheng, Ching-Wei;Lin, Meng-Jau;Shen, Che-Kun James
TDP-43是一种多功能的RNA/DNA结合蛋白，在包括哺乳动物和果蝇在内的许多物种中都很保守。然而，它也是与肌萎缩侧索硬化症(ALS)运动神经元变性相关的病理包涵体的主要组成部分。此外，TDP-43是额颞部退行性变FTLD-U亚型的标志性蛋白。目前，还没有治疗这些神经退行性疾病的有效药物。我们描述了一种新的ALS-TDP果蝇模型的产生和鉴定，该模型在温度敏感的运动神经元特异性GAL4的控制下，在成年果蝇中转基因表达TDP-43的正源基因dTDP，从而绕过了dTDP在发育过程中的有害影响。在诱导dTDP过表达后，观察到苍蝇的寿命缩短以及运动活动受损。解剖胸神经节的T1/T2区发现了这些神经元的丢失。针对ALS-TDP这一果蝇模型的缺陷，我们检测了自噬激活剂雷帕霉素的治疗效果。虽然对对照果蝇有害，但在诱导dTDP过表达之前给予400亩M雷帕霉素可显著减少携带dTDP(+)聚集体的神经元数量，并部分挽救ALS-TDP果蝇寿命缩短和运动缺陷。此外，我们还发现TOR途径的下游调节因子S6K是dTDP的一个遗传修饰物。总之，在时间和空间控制下的ALS-TDP果蝇模型为ALS治疗药物的筛选和验证提供了一个有用的新的遗传学工具。此外，这些数据支持我们之前的发现，即包括雷帕霉素在内的自噬激活剂是治疗伴有TDP-43蛋白病变的神经退行性疾病的潜在治疗药物。
TDP-43 is a multi-functional RNA/DNA-binding protein, well-conserved among many species including mammals and Drosophila. However, it is also a major component of the pathological inclusions associated with degenerating motor neurons of amyotrophic lateral sclerosis (ALS). Further, TDP-43 is a signature protein in one subtype of frontotemporal degeneration, FTLD-U. Currently, there are no effective drugs for these neurodegenerative diseases. We describe the generation and characterization of a new fly model of ALS-TDP with transgenic expression of the Drosophila ortholog of TDP-43, dTDP, in adult flies under the control of a temperature-sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. Diminished lifespan as well as impaired locomotor activities of the flies following induction of dTDP overexpression have been observed. Dissection of the T1/T2 region of the thoracic ganglia has revealed loss of these neurons. To counter the defects in this fly model of ALS-TDP, we have examined the therapeutic effects of the autophagy activator, rapamycin. Although harmful to the control flies, administration of 400 mu M rapamycin before the induction of dTDP overexpression can significantly reduce the number of neurons bearing dTDP (+) aggregates, as well as partially rescue the diminished lifespan and locomotive defects of the ALS-TDP flies. Furthermore, we identify S6K, a downstream mediator of the TOR pathway, as one genetic modifier of dTDP. In sum, this Drosophila model of ALS-TDP under temporal and spatial control presents a useful new genetic tool for the screening and validation of therapeutic drugs for ALS. Furthermore, the data support our previous finding that autophagy activators including rapamycin are potential therapeutic drugs for the progression of neurodegenerative diseases with TDP-43 proteinopathies.