Torsin Function in Drosiphila

torsinA蛋白作为早发性全身性肌张力障碍的原因的发现，为理解这种重要的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蛋白鉴定出一个高度保守的基因家族的事实表明，它们实现了许多生物体中共有的关键功能。扭转蛋白家族成员的结构特征将其置于伴侣样蛋白AAA+家族中，并结合对人类、小鼠和C中扭转蛋白的初步观察。elegans的研究表明，这些蛋白质可能在内质网中正常发挥作用，介导蛋白质和/或脂质货物的有效运动和递送。在扭转蛋白A的羧基末端区域的两个不同的框内改变的描绘，可以产生 肌张力障碍提出了几个明显的问题：扭转蛋白的正常功能是否真的与有效的膜运输有关？肌张力障碍是由显性功能丧失还是功能获得引起的？扭转蛋白突变体的影响能被缓和吗？目前的建议的目标是利用果蝇遗传分析的巨大力量和灵活性来探索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，克隆和表达果蝇torsin（Dtorsin），一个339个氨基酸的蛋白质，显示34%的同一性和56%的相似性与人类torsinA，其最近的人类亲属的序列。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途径。 我们打算探索上述关键问题，使用与异常表达torsin在果蝇的表型，并期望我们的研究将与torsin在人类，小鼠和其他生物体的分析互动，协同影响，特别是在定义正常功能和遗传修饰剂的领域。

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.