This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.DYT1 dystonia is an autosomal dominant disease caused by a three base pair deletion in the TOR1A gene. This mutation removes a codon (gag; E) that normally encodes a glutamic acid residue in torsinA. Although torsinA is broadly expressed, DYT1 dystonia manifests as abnormal, involuntary twisting movements reflecting selective dysfunction of CNS motor circuits. Thus, elucidating the pathogenesis of DYT1 dystonia depends upon defining torsinA-related molecular pathways and cellular processes, including potentially unique events in neurons. TorsinA is a AAA+ protein resident within the endoplasmic reticular (ER)/nuclear envelope (NE) lumen. In previous work, we and others have presented evidence in vitro suggesting that torsinA functions in the NE, including the identification of two torsinA-interacting proteins within the ER/NE luminal space. Our in vivo mutant mouse data are strongly supportive of this notion, demonstrating that loss of torsinA function leads to nuclear membrane abnormalities. Loss-of-function torsinA phenotypes are linked to DYT1 dystonia because the E mutation markedly impairs torsinA function and DYT1 patients have reduced levels of torsinA. This link is further strengthened by the fact that the mouse nuclear membrane abnormalities and human disease symptoms both exhibit neuronal selectivity and developmental dependence. Therefore, we believe that understanding the neurobiological consequences of loss of torsinA function and the mechanism of NE vesicle genesis are likely to provide insight of relevance to disease pathogenesis. With Drs. Perkins and Ellisman, we use electron microscope tomography to study the structural features of NE membrane abnormalities in torsinA mutant mice. Electron tomography is a powerful 3-D imaging tool recognized as a runner-up breakthrough of the year by SCIENCE magazine for 2002 because of its emergence as the leading method for the elucidation of 3D ultrastructure of cells, organelles, and macromolecular complexes at relatively high resolution. The National Center for Microscopy and Imaging Research is an advanced tomography resource that is being extensively used to generate tomographic data for this study.
Showing the most recent 10 out of 384 publications
