PDF(Pubmed)
Abstract：
Mutations in the Transport and Golgi Organization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model of TANGO2-related disease in the fruit fly Drosophila melanogaster that recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated with TANGO2 deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss-of-function in Drosophila and rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2-deficiency disease. Possible mechanisms for the rescue are discussed that may include restoration of lipid homeostasis.
摘要：
运输和高尔基组织2（TANGO2）基因的突变与智力缺陷有关，神经发育迟缓和退化。个体也可出现急性代谢危象，包括横纹肌溶解症，心肌病和心律失常,后者可能是致命的。虽然预防代谢危机有可能降低死亡率，目前没有针对这种情况的治疗方法。TANGO2的功能尚不清楚，但怀疑与脂质代谢的某些方面有关。这里,我们描述了果蝇果蝇中TANGO2相关疾病的模型，该模型概括了关键的疾病特征。将新的苍蝇模型与人体细胞配对,我们检查了维生素B5，辅酶A（CoA）前体，减轻与TANGO2缺乏相关的细胞和生物体缺陷。我们证明，维生素B5特异性改善了果蝇中与TANGO2功能丧失相关的多种缺陷，并挽救了人类细胞中的膜运输缺陷。我们还观察到维生素B3对一种苍蝇缺陷的部分挽救，尽管程度低于维生素B5。我们的数据表明，含有维生素B5/泛酸的B复合物补充剂可能对TANGO2缺乏症患者具有治疗益处。讨论了可能的挽救机制，可能包括恢复脂质稳态。本文受版权保护。保留所有权利。
