the team of the dystonia research group

Dystonia

Dystonia is a neurological movement disorder characterized by involuntary muscle contractions, which force certain parts of the body into abnormal, sometimes painful, movements or postures. Dystonia can affect any part of the body including the arms and legs, trunk, neck, eyelids, face, or vocal cords. A substantial subset of dystonias have an underlying genetic basis with monogenic inheritance in the early onset sever forms and potential susceptibility factors in the focal adult onset forms. Currently, at least more than 20 different types of dystonias can be distinguished genetically associated with different phenotypic presentations.

TorsinA - Dr. Kathrin Grundmann-Hauser

Primary torsion dystonia (PTD), also referred to as early-onset general torsion dystonia, is the most common and severe hereditable form of the disease. PTD is caused by a single mutation in the DYT1 gene (torsinA gene, TOR1A) on chromosome 9 and is transmitted as an autosomal dominant trait with reduced penetrance of 30-40%. It is assumed that the same mutation in the DYT1 gene appeared independently in several ethnic populations throughout history and is possibly one of only a few mutations that result in primary torsion dystonia.

How the abnormal gene causes the dystonia is presently unknown.

The main focus of our research is to further evaluate the precise cellular function of the wildtype protein and to understand the pathogenic mechanism, by which mutant torsinA causes the disease.

We developed several transgenic mouse models which allow us to investigate the features of the disease in vivo and to test for therapeutic strategies. We further generated the first transgenic rat model overexpressing mutant torsinA. By this approach we established a second species besides the mouse for pre-clinical drug studies, and provide a model superior to mice for electrophysiological analysis, for behavioural testing, for in vivo follow-ups of biomarkers such as transcriptome analysis, for siRNA application, and for neurotransplantation.

Low penetrance and phenotypic variability lead to the suggestion that alteration of torsinA amino acid sequence is necessary but not sufficient for development of clinical symptoms and that additional factors (i.e., modifier loci) must contribute to the factual manifestation of the disease. Therefore, to further evaluate the etiopathogenesis of the disease, a second focus of our group lays on identification of interaction partners of torsinA and of intracellular pathways in which torsinA is involved in.

TorsinB - PD Dr. Thomas Ott

TorsinB belongs to the torsin family of proteins which consists of TorsinA, TorsinB, torp2a and torp3a. TorsinB is highly homologous to TorsinA and located adjacent to DYT1 encoding torsinA on chromosome 9. The two proteins have several important features in common including structural domains such as a signal sequence, an ATP binding site and a hydrophobic, potentially membrane spanning domain. Thus, it is reasonable to assume that they have similar properties and functions.

The distinct expression pattern of the two proteins suggests that they share redundant functions and that high levels of TorsinB enable compensate TorsinA function in cells lacking this protein.

In order to better understand the function of TorsinB, we generate and characterize neuronal and non-neuronal cell lines as well as mouse models lacking TorsinB.