Torsin Function in Drosiphila

TorsinA蛋白是早发性全身性肌张力障碍的病因，这一发现为理解这一重要疾病和根据其发病机制开发有效的治疗方法提供了令人兴奋的新可能性。Torsin蛋白识别高度保守的基因家族的事实表明，它们履行着许多生物体共有的关键功能。根据Torsin家族成员的结构特征，将它们归入AAA+类伴侣蛋白家族，并结合对人、小鼠和线虫Torsins的初步观察，表明这些蛋白可能在内质网中正常发挥功能，介导蛋白质和/或脂肪货物的有效移动和运输。Torsin A羧基末端区域两种不同的框内改变的描绘 肌张力障碍提出了几个明显的问题：扭力的正常功能是否真的与有效的膜运输有关？肌张力障碍是由主导性功能丧失还是功能获得引起的？突变型Torsin的影响能被缓和吗？目前这项提议的目的是利用果蝇遗传分析的巨大能力和灵活性来探索Torsin蛋白的正常和异常功能。在我们的初步工作中，我们已经定义、克隆和表达了果蝇Torsin(Dtorsin)，它是一种339个氨基酸的蛋白质，与其最接近的人类近亲人类Torsin A的序列有34%的同源性和56%的相似性。由于在果蝇基因组中只有一个Torsin基因座，这为探索该基因家族的功能提供了一条理想的遗传路线。 我们打算利用果蝇中与Torsin异常表达相关的表型来探索上述关键问题，并期待我们的研究将与对人类、小鼠和其他生物中Torsin的分析互动地进行，产生协同影响，特别是在定义正常功能和遗传修饰物方面。

The discovery of the torsinA protein as the cause of early onset generalized dystonia offers exciting new possibilities for understanding this important disorder and for developing effective treatments based on its mode of pathogenesis. The fact that the torsin proteins identify a highly conserved gene family suggests that they fulfill a critical function shared in many organisms. Structural features of the torsin family members, place them in the AAA+ family of chaperone-like proteins and, combined with initial observations of torsins in human, mouse and C. elegans, suggest that these proteins may normally function in the endoplasmic reticulum in mediating efficient movement and delivery of protein and/or lipid cargoes. The delineation of two different in-frame alterations in the carboxyl-terminal region of torsinA that can produce dystonia raises several obvious questions: Is the normal function of the torsins indeed related to efficient membrane trafficking? Does dystonia result from a dominant loss-of-function or gain-of-function? Can the effects of mutant torsin be moderated? The goal of the current proposal is to take advantage of the tremendous power and flexibility of genetic analysis in Drosophila to explore the normal and abnormal function of the torsin proteins. In our preliminary work we have defined, cloned and expressed Drosophila torsin (Dtorsin), a 339 amino acid protein that shows 34% identity and 56% similarity with the sequence of human torsinA, its closest human relative. As there is only a single torsin locus in the Drosophila melanogaster genome, it presents an ideal genetic route for exploring the function of this gene family. We intend to explore the critical questions above using phenotypes associated with aberrant expression torsin in Drosophila, and expect that our studies will progress interactively with analysis of torsin in human, mouse and other organisms, with a synergistic impact, particularly in the areas of defining normal function and genetic modifiers.