Get access

Engineering animal models of dystonia

Authors


  • Supported by grants from the Tyler's Hope for a Dystonia Care, Inc., the National Institutes of Health (NS37409, NS47466, NS47692, NS54246, NS57098, NS65273, NS72872, and NS74423), and startup funds from the Departments of Neurology at UAB and UF (Yuqing Li).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full author roles may be found in the Acknowledgments section online.

Correspondence to: Dr. Yuqing Li, Department of Neurology, College of Medicine, University of Florida, PO Box 100236, Gainesville, FL 32610; yuqing.li@neurology.ufl.edu

ABSTRACT

Dystonia is a neurological disorder characterized by abnormal involuntary movements that are prolonged and often cause twisting and turning. Several genetically modified worms, fruit flies, and rodents have been generated as models of genetic dystonias, in particular DYT1, DYT11, and DYT12 dystonias. Although these models do not show overt dystonic symptoms, the rodent models exhibit motor deficits in specialized behavioral tasks, such as the rotarod and beam-walking tests. For example, in a rodent model of DYT12 dystonia, which is generally stress triggered, motor deficits are observed only after the animal is stressed. Moreover, in a rodent model of DYT1 dystonia, the motor and electrophysiological deficits can be rescued by trihexyphenidyl, a common anticholinergic medication used to treat dystonic symptoms in human patients. Biochemically, the DYT1 and DYT11 animal models also share some similarities to patients, such as a reduction in striatal D2 dopamine receptor and binding activities. In addition, conditional knockout mouse models for DYT1 and DYT11 dystonia demonstrate that loss of the causal dystonia-related proteins in the striatum leads to motor deficits. Interestingly, loss of the DYT1 dystonia causal protein in Purkinje cells shows an improvement in motor performance, suggesting that gene therapy targeting of the cerebellum or intervention in its downstream pathways may be useful. Finally, recent studies using DYT1 dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials. These results indicate that genetic animal models are powerful tools to elucidate the pathophysiology and to further develop new therapeutics for dystonia. © 2013 Movement Disorder Society

Get access to the full text of this article

Ancillary