DYT1 dystonia is a neurodevelopmental disease caused by a deletion (?gag;?E) in the Tor1a gene encoding torsinA. Although this mutation was discovered in 1997, it is unknown whether the ?E mutation causes abnormal movements though a gain or loss of function mechanism. Confounding this issue, it is unclear when the ?E mutation disrupts development and function of the motor system. These questions are conceptually and practically important because their answers are urgently needed to advance understanding of dystonia pathogenesis and to begin to design rationally targeted therapies (e.g., knowing that torsinA loss of function causes abnormal movement would suggest a search for torsinA-activating compounds). A major barrier to unraveling the mechanism of the ?E mutation that causes dystonia is the absence of a torsinA-based mouse model that develops overt abnormal movements. In this application, we describe the development of the first such model with overt dystonic-like twisting movements. Moreover, we have developed a related set of torsinA-based mouse models that will enable us to delete torsinA or induce the endogenous expression of ?E-torsinA in the developing or mature CNS. Our extensive preliminary data based on these models has already enabled us to make a series of exciting observations linking the ?E mutation, torsinA loss- of-function, motor circuit-selective molecular pathology and abnormal twisting movements. These data also identify the torsinA homolog torsinB as a powerful modulator of torsinA phenotypes, providing mechanistic insight into dystonia pathogenesis. We propose to use these novel models 1) to define the mechanism of the ?E mutation that causes abnormal movements;2) to determine when during neural development the critical events occur and;3) to test the hypothesis that torsinB is a critical determinant of CNS sensitivity to torsinA dysfunction that can be used to suppress or prevent DYT1 dystonia.
DYT1 dystonia is an incurable brain disease of childhood caused by a mutation in the gene encoding the torsinA protein. The effect of this mutation on torsinA function is unknown. This proposal employs novel mouse models of DYT1 dystonia to determine the effect of the DYT1 mutation on torsinA function, and tests a novel approach to prevent or suppress the symptoms of the disease.
|Pappas, Samuel S; Liang, Chun-Chi; Kim, Sumin et al. (2018) TorsinA dysfunction causes persistent neuronal nuclear pore defects. Hum Mol Genet 27:407-420|
|Pappas, Samuel S; Li, Jay; LeWitt, Tessa M et al. (2018) A cell autonomous torsinA requirement for cholinergic neuron survival and motor control. Elife 7:|
|Saunders, Cosmo A; Harris, Nathan J; Willey, Patrick T et al. (2017) TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement. J Cell Biol 216:657-674|
|Yellajoshyula, Dhananjay; Liang, Chun-Chi; Pappas, Samuel S et al. (2017) The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage. Dev Cell 42:52-67.e4|
|DeSimone, Jesse C; Pappas, Samuel S; Febo, Marcelo et al. (2017) Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia. Neurobiol Dis 106:124-132|
|Tanabe, Lauren M; Liang, Chun-Chi; Dauer, William T (2016) Neuronal Nuclear Membrane Budding Occurs during a Developmental Window Modulated by Torsin Paralogs. Cell Rep 16:3322-3333|
|Kett, Lauren R; Dauer, William T (2016) Endolysosomal dysfunction in Parkinson's disease: Recent developments and future challenges. Mov Disord 31:1433-1443|
|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|
|VanGompel, Michael J W; Nguyen, Ken C Q; Hall, David H et al. (2015) A novel function for the Caenorhabditis elegans torsin OOC-5 in nucleoporin localization and nuclear import. Mol Biol Cell 26:1752-63|
|Pappas, Samuel S; Darr, Katherine; Holley, Sandra M et al. (2015) Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons. Elife 4:e08352|
Showing the most recent 10 out of 19 publications