The goal of my dissertation work was to examine the systems biology of torsinA, a DYT1 dystonia-associated protein, by using rodent model systems. TorsinA is a putative A&barbelow;TPase a&barbelow;ssociated with a variety of cellular activities (AAA+). Deletion of glutamic acid residue 302/303 in TOR1A is causally associated with many cases of early-onset primary dystonia.

In our work, transient forebrain ischemia and sciatic nerve transection were used as central and peripheral neural perturbations, respectively, to gain insight into the in vivo role(s) of torsinA. Moreover, transgenic mouse models that overexpress either human mutant torsinA (hMT) or wild-type torsinA (hWT) were used to analyze the behavioral, morphological, neurochemical, and brain metabolical consequences of increased mutant torsinA burden.

After transient forebrain ischemia and sciatic nerve transection, torsinA expression levels were temporally increased in both the central and peripheral nervous systems. In the hippocampus and dorsal root ganglion, increased torsinA immunoreactivity was found located in neuronal populations such as projection neurons, interneurons, and ganglion cells, and in glial elements such as reactive astrocytes and satellite cells. These results suggest that torsinA participates in the response of neural tissue to central and peripheral insults, and that limited recruitment of intact functional torsinA might contribute to the onset of DYT1 dystonia in TOR1A ΔGAG mutation carriers. The striking induction of torsinA in astrocytes and satellite cells points to the potential involvement of glial elements in the pathobiology of DYT1 dystonia.

In the DYT1 transgenic mice, mutant torsinA burden resulted in prolonged traversal times and more slips on a raised-beam task; widened hind-base width; increased dopamine turnover in the striatum, and a shift in brain energy demand from the basal ganglia to olivocerebellar pathways. However, no morphological alterations were detected in the mutant mice with either light or electron microscopy. Our neurochemical findings in DYT1 transgenic mice are compatible with previous postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in torsinA mutant mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia. The relatively attenuated energy demand in basal ganglion output regions may be a manifestation of a primary functional abnormality in the nigrostriatal system of DYT1 mutation carriers and the relatively elevated energy demand in cerebellar cortex might be a compensatory response to dysfunction of the basal ganglia.