Animal Models of Dystonia – Part I

An invited post by Erwin Montgomery, M.D., and Michele A. Basso, Ph.D., University of Wisconsin, Madison.

Dystonia is a neurological disorder of movement characterized by sustained muscle contractions affecting one or more sites of the body. Dystonia frequently causes twisting and repetitive movements and abnormal postures resulting in relentless pain. If dystonia affects one part of the body it is called focal. If dystonia affects more than one site in the body it is referred to as generalized dystonia (see video below). Although generalized dystonia is a relatively rare disease, a familiar example of a focal dystonia is writer’s cramp. Dystonia may be inherited or caused by trauma at birth, by infection, by poisoning or may be drug induced such as occurs sometimes with neuroleptic treatment for psychotic symptoms. The main treatment available for dystonia is pharmacological and provides relief of symptoms only, often with serious side-effects. There is no cure for dystonia.

Dystonia is associated with a number of genetic mutations in humans. For example, DYT1 dystonia is caused by a mutation in the TOR1A gene. In its mutated form associated with dystonia, the gene has a unique 3-base pair deletion. This gene encodes for the production of a protein called Torsin A. When the protein is produced by the mutated gene it is missing one of a pair of glutamic acid residues making it function abnormally. DYT1 is inherited in an autosomal dominant manner with reduced penetrance. This means that the offspring of an affected individual or an asymptomatic individual known to have a TOR1A mutation have a 50% chance of inheriting the mutation and a 30% to 40% chance of developing symptoms of dystonia. The occurrence of the DYT1 mutation is relatively rare, less than 1% of the overall population carries the mutated gene. Interestingly, among Ashkenazi Jews, the frequency is at least 3-5 times higher.

Since the discovery of the mutation in the TOR1A gene there have been many studies in animals designed to understand the role of the gene and its protein product, Torsin A in producing the disease. As a result of the discovery of the gene, researchers have been able to produce rodent models that express the mutated gene. This allows a detailed study of the role of the protein in the function of the whole animal. The discovery of the gene also allowed cell culture models to be developed in order to study the fundamental cellular biology of the protein that is implicated in producing the symptoms of dystonia. For example, animals with the mutated gene allowed for the discovery of where in the body the product of the gene was localized. We now know that Torsin A appears in brain cells and acts as a chaperone protein, assisting other cellular proteins to reach their final destinations and to form and maintain their 3D structure within cells. Torsin A plays a critical role in cellular functions related to the destruction of proteins that may be harmful to cells as well as the movement of organelles throughout the cell. This latter role for Torsin A may be most critical during the development of the brain and current research is suggesting that this role may hold the key to unlocking the mystery of how Torsin A results in the devastating symptoms of dystonia. Using this knowledge cell culture models are being developed in which drugs that target particular cellular functions can be assessed for their viability as a treatment for the disease symptoms.

Genetic models in rodents also led to the finding that the electrophysiological properties of brain circuits are malfunctioning in dystonia. One model of how dystonia arises is through a faulty learning mechanism – or faulty neuroplasticity. In a region of the brain called the basal ganglia, some neurons contain the neurotransmitter dopamine. This neurotransmitter is thought to play a role in certain types of learning. The cerebral cortex communicates with another region of the basal ganglia called the striatum. A simple model for how learning takes place in this circuit is that when signals from the cerebral cortex to the striatum are activated and there is a simultaneous signal from the dopamine neurons to this cortico-striatal synapse, behavior is enhanced or learned. If dopamine binds to one type of receptor the efficacy of the cortico-striatal synapse is reduced and the behavior is minimized or unlearned. If dopamine binds to a second receptor type the efficacy of the cortico-striatal synapse is enhanced and the behavior is learned. A second neurotransmitter called acetylcholine interacts with dopamine to either increase or decrease the likelihood of this plasticity taking place. Using animal models scientists have discovered that these different receptor types are localized to different neuronal cell types within the striatum and that acetylcholine is localized in one particular neuronal cell type within the basal ganglia, thus giving rise to different circuits involved in learning and unlearning behaviors. Interestingly, this type of neuroplasticity is altered in the brain of rodents containing the mutated gene that results in dystonia in humans. Indeed, in recent experiments using similar measures of neuroplasticity in humans reveals that patients with dystonia often have faulty neuroplasticity. A wonderful review of the confluence of human and animal studies revealing the learning and plasticity alterations in patients with dystonia appears in a recent paper.

In the next part of this post we will explore how, based in part from the findings rodent models, a primate model of dystonia was developed and how such work is bringing hope to dystonia patients worldwide.