Torsin Function in Drosiphila

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

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.