Early-onset dystonia (DYT1) is caused by an autosomal dominant mutation in the torsinA protein. Dystonia is manifested by sustained muscle contractions, appearing as movements or abnormal postures, which may be focal or diffuse. TorsinA expression is diffuse within both the central nervous system and peripheral organs. Therefore, similar to many other neurologic diseases, it is important to determine how a diffusely expressed protein can cause localized disease. In the case ofdystonia, extensive evidence points to a key, although not necessarily unique, dysfunction within the basal ganglia. With recent progress in this laboratory in the identification ofa striatal specific promoter active in transgenic mice, along with the expertise of collaborators, this group of investigators is in a unique position to test hypotheses regarding the role of the basal ganglia in dystonia. Simultaneously, testing of these hypotheses may lead to valuable animal models of the disease. This is an R21 proposal to create these transgenic models.
Specific Aim 1 is to create transgenic mice expressing mutated human torsin A in the l) substantia nigra, under the direction of the human tyrosine hydroxylase promoter and 2) in the striatum, under the direction of the mouse DARPP-32 promoter.
SPECIFIC AIM 2 is to initiate the analysis of these mice, and to determine whether selective expression of torsinA in the substantia nigra and/or striatum results in 1) a movement disorder in transgenic mice, as determined by rotarod testing and/or 2) abnormalities ofdopaminergic neurotransmission in the striatum, as determined by induction of c-los expression following administration ofa psycho stimulant, i.e. a dopamine agonist.
| Martin, J N; Wolken, N; Brown, T et al. (2011) Lethal toxicity caused by expression of shRNA in the mouse striatum: implications for therapeutic design. Gene Ther 18:666-73 |
| Page, Michelle E; Bao, Li; Andre, Pierrette et al. (2010) Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (DeltaE) TorsinA in transgenic mice. Neurobiol Dis 39:318-26 |
