Abstract

? Early onset torsion dystonia is the most common and severe form of inherited dystonia. Many cases of this disease are associated with a single amino acid deletion in the protein torsinA. TorsinA is an AAA+ ATPase found in the endoplasmic reticulum, but its normal cellular function and role in the pathogenesis of dystonia are unknown. The goal of this project is to define cellular and molecular events controlled by torsinA in order to begin to understand the etiology of this elusive disease. In preliminary studies, we used torsinA mutants expressed in cultured cells and identified a likely function for torsinA in a subdomain of the ER, the nuclear envelope. Experiments in this proposal will explore how torsinA functions as an AAA+ ATPase and define its exact role in the nuclear envelope. ? Our specific aims are: ? 1. To develop and experimentally test a structural model for torsinA function, and then apply this to understanding how disease-linked mutations affect protein function. ? 2. To study torsinA dynamics and distribution in the endoplasmic reticulum and nuclear envelope to test the hypothesis that the nuclear envelope is its primary site of action. ? 3. To define the molecular targets of torsinA in the nuclear envelope. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050717-04
Application #
7262442
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Tagle, Danilo A
Project Start
2004-07-01
Project End
2010-12-31
Budget Start
2007-07-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$268,383
Indirect Cost

  Institution

Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Grillet, Micheline; Dominguez Gonzalez, Beatriz; Sicart, Adria et al. (2016) Torsins Are Essential Regulators of Cellular Lipid Metabolism. Dev Cell 38:235-47
McCullough, John; Clippinger, Amy K; Talledge, Nathaniel et al. (2015) Structure and membrane remodeling activity of ESCRT-III helical polymers. Science 350:1548-51
Goodchild, Rose E; Buchwalter, Abigail L; Naismith, Teresa V et al. (2015) Access of torsinA to the inner nuclear membrane is activity dependent and regulated in the endoplasmic reticulum. J Cell Sci 128:2854-65
Vander Heyden, Abigail B; Naismith, Teresa V; Snapp, Erik L et al. (2011) Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum. EMBO J 30:3217-31
Naismith, Teresa V; Dalal, Seema; Hanson, Phyllis I (2009) Interaction of torsinA with its major binding partners is impaired by the dystonia-associated DeltaGAG deletion. J Biol Chem 284:27866-74
Vander Heyden, Abigail B; Naismith, Teresa V; Snapp, Erik L et al. (2009) LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol Biol Cell 20:2661-72
Breakefield, Xandra O; Blood, Anne J; Li, Yuqing et al. (2008) The pathophysiological basis of dystonias. Nat Rev Neurosci 9:222-34
Weihl, Conrad C; Miller, Sara E; Hanson, Phyllis I et al. (2007) Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice. Hum Mol Genet 16:919-28
Weihl, Conrad C; Dalal, Seema; Pestronk, Alan et al. (2006) Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet 15:189-99
Kock, Norman; Naismith, Teresa V; Boston, Heather E et al. (2006) Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier. Hum Mol Genet 15:1355-64