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TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity.
BMC Biology ( IF 5.4 ) Pub Date : 2020-07-03 , DOI: 10.1186/s12915-020-00816-1
Giulia Romano 1 , Raffaella Klima 1 , Fabian Feiguin 1
Affiliation  

Mutations in the small RNA-binding protein TDP-43 lead to the formation of insoluble cytoplasmic aggregates that have been associated with the onset and progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting homeostasis of the motor system which is also characterized by aberrant expression of retrotransposable elements (RTEs). Although the TDP-43 function was shown to be required in the neurons and glia to maintain the organization of neuromuscular synapses and prevent denervation of the skeletal muscles, the molecular mechanisms involved in physiological dysregulation remain elusive. Here, we address this issue using a null mutation of the TDP-43 Drosophila homolog, TBPH. Using genome-wide gene expression profiles, we detected a strong upregulation of RTE expression in TBPH-null Drosophila heads, while the genetic rescue of the TDP-43 function reverted these modifications. Furthermore, we found that TBPH modulates the small interfering RNA (siRNA) silencing machinery responsible for RTE repression. Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposon activation and promote motoneuron axonal wrapping and synaptic growth in TBPH-null Drosophila. We identified an upregulation of RTE expression in TBPH-null Drosophila heads and demonstrate that defects in the siRNA pathway lead to RTE upregulation and motoneuron degeneration. Our results describe a novel physiological role of endogenous TDP-43 in the prevention of RTE-induced neurological alterations through the modulation of Dicer-2 activity and the siRNA pathway.

中文翻译:

TDP-43通过调节Dicer-2的活性来防止果蝇运动系统中的反转录转座子激活。

小RNA结合蛋白TDP-43中的突变导致形成不溶性细胞质聚集体,与肌萎缩性侧索硬化症(ALS)的发作和发展有关,肌萎缩性侧索硬化症是一种影响运动系统稳态的神经退行性疾病,其特征还在于逆转座因子(RTE)的异常表达。尽管已显示在神经元和神经胶质中需要TDP-43的功能来维持神经肌肉突触的组织并防止骨骼肌的神经支配,但是涉及生理失调的分子机制仍然难以捉摸。在这里,我们使用TDP-43果蝇同源物TBPH的无效突变来解决此问题。使用全基因组的基因表达谱,我们检测到在TBPH无果蝇头部中RTE表达强烈上调,TDP-43功能的基因拯救恢复了这些修饰。此外,我们发现TBPH调节负责RTE抑制的小干扰RNA(siRNA)沉默机制。在分子上,我们观察到TBPH通过体内的直接蛋白质-mRNA相互作用调节Dicer-2的表达水平。因此,Dicer-2活性的遗传或药理学恢复足以抑制逆转录转座子的活化并促进TBPH无果蝇中的运动神经元轴突包裹和突触生长。我们发现TBPH空果蝇头中RTE表达的上调,并证明siRNA途径中的缺陷导致RTE上调和运动神经元变性。
更新日期:2020-07-03
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