, Volume 9, Issue 2, pp 315-322
Date: 16 Mar 2012

Alternative Approaches to Modeling Hereditary Dystonias


Dystonia is a movement disorder characterized by involuntary muscle contractions resulting in abnormal postures. Although common in the clinic, the etiology of dystonia remains unclear. Most dystonias are idiopathic and are not associated with clear pathological brain abnormalities. Attempts to genetically model these dystonias in rodents have failed to replicate dystonic symptoms. This is at odds with the fact that rodents can exhibit dystonia. Because of this discrepancy, it is necessary to consider alternative approaches to generate phenotypically and genotypically faithful models of dystonia. Conditional knockout of dystonia-related genes is 1 technique that may prove useful for modeling genetic dystonias. Lentiviral-mediated small or short hairpin RNA (shRNA) knockdown of particular genes is another approach. Finally, in cases in which the function of a dystonia-related gene is well-known, pharmacological blockade of the protein product can be used. Such an approach was successfully implemented in the case of rapid-onset dystonia parkinsonism, DYT12. This (DYT12) is a hereditary dystonia caused by mutations in the α3 isoform of the sodium potassium adenosine triphosphatase (ATPase) pump (sodium pump), which partially hampers its physiological function. It was found that partial selective pharmacological block of the sodium pumps in the cerebellum and basal ganglia of mice recapitulates all of the salient features of DYT12, including dystonia and parkinsonism induced by stress. This DYT12 model is unique in that it faithfully replicates human symptoms of DYT12, while targeting the genetic cause of this disorder. Acute disruption of proteins implicated in dystonia may prove a generally fruitful method to model dystonia in rodents.