Pathophysiology of DYT1 Dystonia: Targeted Mouse Models

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DESCRIPTION (provided by applicant): Oppenheim's dystonia is a generalized early-onset dystonia. It is an autosomal dominant disorder with reduced penetrance due to a 3-bp deletion (AGAG) that deletes a glutamic acid residue in the coding region of DYT1, which codes for torsinA protein. It is not known what functions torsinA protein serves in the cell, let alone mechanisms of how the mutant torsinA protein could lead to dystonia. The broad, long-term objective is to use transgenic mice to determine: 1) what is the functional role of torsinA in vivo? 2) How does the mutant torsinA protein lead to early onset dystonia? The objective of this application is to analyze Dyt1 AGAG knock-in mice that we have created to test the hypotheses that DYT1 AGAG mutation is a loss- or reduction-of-function mutation that disrupts dopaminergic modulation of corticostriatal pathway, which in turn leads to an abnormal control of movement and posture. Here we propose to test the hypothesis that DYT1 AGAG mutation leads to a loss- or reduction-of-function, and not a toxic gain-of-function, we will determine the relative motor performance, neurochemistry, neuropathology, and electrophysiology of three lines of transgenic mice with altered level of wild-type (WT) and mutant torsinA proteins. We will determine if varying levels of WT torsinA protein in the presence of a mutant torsinA alter mutant mice's motor behaviors, neurochemistry, neuropathology and electrophysiology. Furthermore, to test the hypothesis that Dyt1 AGAG mutation disrupts dopaminergic function especially D2 receptor pathway, we will measure and compare the various aspects of the dopaminergic system in Dyt1 AGAG knockin and wild-type mice. These studies will increase the understanding about the function of normal torsinA, the role of mutant torsinA in the pathophysiology of dystonia, and the mechanism through which the neural interference is caused by mutant torsinA. With this understanding, new and creative therapies can be devised to combat the debilitating symptoms caused by DYT1 dystonia.