This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The torsins are an ancient family of well-conserved AAA+ proteins present within the endoplasmic reticular/nuclear envelope (ER/NE) lumen. TorsinA functions in the NE, where it interacts with LAP1 (lamina-associated protein 1). DYT1 dystonia is a neurodevelopmental disease caused by an in-frame deletion (?gag;?E) in the gene encoding torsinA. Although torsinA is ubiquitously expressed, DYT1 dystonia is a neural-selective disorder. Thus, deciphering the molecular events underlying DYT1 dystonia will not only yield information necessary for rational treatment of the disease, but also provide insight into previously unrecognized processes required for normal neuronal function. The DYT1 mutation impairs torsinA function, and loss of this function in mice causes vesiculation of neuronal nuclear envelope membranes (NE """"""""blebs""""""""). TorsinA null (Tor1a-/-) and disease knock-in (Tor1aE/E) mice both exhibit NE blebs, which appear to be outpouchings of the inner nuclear membrane (INM). Like the disease, NE blebs are neural-specific. Overexpression of LAP1 also causes NE blebs, linking LAP1 and torsinA function. AAA+ proteins modify protein substrates, typically unfolding proteins or disassembling protein complexes. Therefore, we hypothesize that the phenotype of Tor1a mutant mice reflects the failure of an AAA+ protein (torsinA) to act on its substrate (LAP1). Based on these data, we believe that understanding the mechanisms underlying NE bleb genesis may provide insight relevant to disease pathogenesis and torsinA function. The objective of this project is to use electron microscope (EM) tomography and immuno-electron microscopy to determine whether NE blebs originate from the nuclear pore. This question has implications for the pathogenesis of DYT1 dystonia and may implicate torsinA function in nuclear pore biogenesis, about which little is known.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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University of California San Diego
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