Microsatellite expansions of CCTG repeats in the cellular nucleic acid-binding protein (CNBP) gene leads to accumulation of toxic RNA and have been associated with myotonic dystrophy type 2 (DM2). However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA-binding protein that regulates translation and is required for mammalian development. Here, we show that depletion of Drosophila CNBP in muscles causes ageing-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscles from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.

中文翻译：

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果蝇运动功能需要 CNBP 对多胺代谢的转化控制

细胞核酸结合蛋白 ( CNBP ) 基因中 CCTG 重复序列的微卫星扩增导致有毒 RNA 的积累，并与 2 型肌强直性营养不良 (DM2) 相关。然而，目前尚不清楚营养不良表型是否也与 CNBP 减少有关，CNBP 是一种保守的 CCHC 型锌指 RNA 结合蛋白，可调节翻译并且是哺乳动物发育所必需的。在这里，我们表明果蝇的消耗肌肉中的 CNBP 会导致衰老相关的运动缺陷，这些缺陷与多胺代谢受损有关。我们证明鸟氨酸脱羧酶 (ODC) 和多胺的水平在 dCNBP 消耗后显着降低。值得注意的是，我们展示了 DM2 患者肌肉中 CNBP-多胺轴的减少。从机制上讲，我们提供证据表明 dCNBP 通过结合 dOdc mRNA 并调节其翻译来控制多胺代谢。值得注意的是，dCNBP 缺陷果蝇的运动缺陷可以通过多胺补充剂或 dOdc1 过度表达来挽救。我们建议这种 dCNBP 功能在脊椎动物中进化保守，对 CNBP 相关的病理生理条件具有相关意义。