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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS077730-02
Application #
8607217
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sieber, Beth-Anne
Project Start
2013-02-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$346,278
Indirect Cost
$123,591
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Pappas, Samuel S; Leventhal, Daniel K; Albin, Roger L et al. (2014) Mouse models of neurodevelopmental disease of the basal ganglia and associated circuits. Curr Top Dev Biol 109:97-169
Maric, Martina; Haugo, Alison C; Dauer, William et al. (2014) Nuclear envelope breakdown induced by herpes simplex virus type 1 involves the activity of viral fusion proteins. Virology 460-461:128-37
Dauer, William T (2014) Neurogenetic disease: genes, mechanisms, and future promise. Neurotherapeutics 11:697-8
Worman, Howard J; Dauer, William T (2014) The nuclear envelope: an intriguing focal point for neurogenetic disease. Neurotherapeutics 11:764-72
Liang, Chun-Chi; Tanabe, Lauren M; Jou, Stephanie et al. (2014) TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration. J Clin Invest 124:3080-92
Dauer, William (2014) Inherited isolated dystonia: clinical genetics and gene function. Neurotherapeutics 11:807-16
Ledoux, Mark S; Dauer, William T; Warner, Thomas T (2013) Emerging common molecular pathways for primary dystonia. Mov Disord 28:968-81
Santos, Mariana; Rebelo, Sandra; Van Kleeff, Paula J M et al. (2013) The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate. PLoS One 8:e76788