? The central goal of this proposal is to delineate the key molecular and cellular mechanisms that produce central nervous system dysfunction in primary dystonia. Primary dystonia is a disease characterized by prolonged involuntary twisting movements, which appears to result from abnormal motor system function in the absence of histopathology. DYT1 dystonia is a dominantly inherited childhood-onset form of primary dystonia caused by a single glutamic acid deletion in torsinA, a endoplasmic reticulum (ER) resident AAA protein of unknown function. Little is understood about the pathogenesis of DYT1 dystonia. Because dystonia is a functional disorder, reliable insight into this problem will require parallel molecular, histological and functional studies. Thus, we generated an allelic series of torsinA mouse mutants (including knock in, knock out and conditional transgenic mice), and a wealth of other complementary reagents. Strikingly, we find abnormalities localized to the nuclear envelope in both torsinA transgenic and null mice: DYT1-torsinA abnormally accumulates in the neuronal nuclear envelope of transgenic mice, and torsinA null mice display marked alterations in NE morphology. DYT1-torsinA also accumulates abnormally in cells from DYT1 patients. So, our torsinA mutant mice model events that are relevant to the human disease. Our hypothesis is that the perinuclear accumulation of DYT1 torsinA is an important pathogenic event in DYT1 dystonia.
In Aim 1 we will characterize the cellular effects of torsinA dysfunction in cell lines and primary neuronal cultures derived from torsinA mutant mice. These experiments will include assays of nuclear and ER function.
In Aim 2 we will perform a variety of neuropathological, neurochemical and ultrastructural studies in an effort to characterize the first animal model of DYT1 dystonia.
In Aim 3 we explore the function of the intact nervous system of torsinA mutant mice with multiple complementary assays. We believe that the results of the work may provide insight into the neurobiology of dystonia and suggest rational avenues for exploring therapy for the disease. ? ?
| Tanabe, Lauren M; Kim, Connie E; Alagem, Noga et al. (2009) Primary dystonia: molecules and mechanisms. Nat Rev Neurol 5:598-609 |
| Goodchild, Rose E; Dauer, William T (2005) The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. J Cell Biol 168:855-62 |
