Collaborative Research Grants 2013-2015

FDR made grants available for collaborative research on primary dystonia and dystonia-plus syndromes. The research should lead to a better understanding of the pathogenesis of dystonia and contribute to improving the diagnosis of the disease and the treatment of persons with dystonia.

Research proposals had to be submitted by at least two collaborating research groups (one coordinating laboratory and one or more partners), with an overall maximum budget of €200 000 (incl. bonus for exchange of researchers). Funding started on January 1, 2014.

In this call, emphasis was placed on fundamental research projects and discovery projects at the molecular, cellular, and/or systems level. Grant applications were internationally peer reviewed by independent reviewers and the FDR scientific committee.

The following submissions were selected for funding:

Using exome sequencing and abnormal temporal discrimination, a mediational endophenotype, to identify new genes in adult onset primary torsion dystonia

Coordinator: Michael Hutchinson, St Vincent's University Hospital, Dept. of Neurology, Elm Park, Dublin, Ireland,

Participating lab: Laurie Ozelius, Massachusetts General Hospital, Boston,USA, previously Icahn School of Medicine at Mount Sinai, New York.

179 000 EUR

The Hutchinson/Ozelius collaboration focuses on the temporal discrimination threshold (TDT), which is the shortest time interval at which two stimuli appear asynchronous. The researchers hypothesize that an abnormal TDT is an endophenotype, a state independent marker of gene carriage in AOPTD. In a series of studies they have determined that an abnormal TDT (Z-score >2.5): a) is highly specific in that it was not found in 192 healthy control participants 18-65 years of age : b) is found in 90% of patients with cervical dystonia : c) appears to be almost fully penetrant in first degree unaffected female relatives after the age of 48 years but only 40% penetrant in first degree unaffected male relatives after 30 years of age. The aims of this research project are (i) to identify, by exome sequencing, genetic mutations responsible for the commonest form of AOPTD, cervical dystonia and (ii) by identifying these mutations to validate the endophenotype. This work will be a collaborative study between Dublin, Ireland (Michael Hutchinson) and New York, USA (Laurie Ozelius).

Towards the molecular basis of early onset dystonia – structural and biochemical analysis of Torsin1A

Coordinator: Ulrike Kutay, ETH Zurich, Department of Biology/Institute of Biochemistry, Zurich, Switzerland,

Participating lab: Thomas U. Schwartz, Massachusetts Institute of Technology (MIT), Department of Biology, Cambridge, MA, USA

200 000 EUR

The Kutay/Schwartz collaboration intends to find and characterize substrate(s) of Torsin1A, characterize the spatiotemporal relationship between wildtype and mutant Torsin1A and its known (LAP1, LULL1) and newly identified binding partners in vivo, and determine the crystal structures of Torsin1A and Torsin1A(ΔE) with and without its binding partners. They will approach the aims using a comprehensive set of cell biological, biochemical, and structural tools. Specifically, they will pursue the first aim using pulldown methods for substrate identification established in the Kutay lab. The interaction of candidate substrates with Torsin1A will be verified by biochemical analysis. For the second aim fluorescent imaging techniques including fluorescence recovery after photobleaching (FRAP) will be employed to investigate the influence of Torsin1A and mutants thereof on the localization and mobility of its interaction partners. Finally the Schwartz lab will use its extensive expertise in X-ray crystallography to tackle the difficult problem of identifying the three dimensional structure of Torsin1A. The two groups have worked together very successfully in the past, and have published important results on the structure and function of the LINC complex, a potential substrate for Torsin1A. 

Assessing the role of dopaminergic signal transduction pathway in primary dystonia

Coordinator: Antonio Pisani, University of Rome Tor Vergata, Department of Systems Medicine, Rome, Italy,

Participating labs: Kathrin Grundmann/Hoa Nguyen, University of Tuebingen, Dept. of Medical Genetics, Tuebingen, Germany and Rose Goodchild, University of Leuven (KU Leuven)/ Vlaams Instituut voor Biotechnologie (VIB), Center for the Biology of Disease, Laboratory of Dystonia Research, Leuven, Belgium.

200 000 EUR

The Pisani/Grundmann/Nguyen/Goodchild collaboration will examine how GNAL deficiency affects striatal electrophysiology and information processing in a novel rat model of primary dystonia, which will accurately model the GNAL+/- insult. Furthermore, they will examine how Rhes/ mTOR signaling controls striatal plasticity by exploring how GNAL deficiency impacts Rhes and mTOR activation. Finally, they will test whether dysfunction of Rhes, mTOR, or other elements of striatal signal transduction are a common node in primary dystonia pathogenesis in existing mouse models of dystonia. The project will benefit from the collaborative work covering different approaches: electrophysiology (Pisani) to detect a functional, synaptic correlate of primary dystonia, molecular genetics and behavioral analysis (Grundmann) and biochemical (Goodchild) characterization, in order to assess the role of dopaminergic dysfunction in dystonia, but also explore the rationale to target dopaminergic signaling pathways for drug development.

‘Special encouragement grant of 20 000 EUR’

Identification of the DYT21 gene by deep sequencing

Coordinator: Monica Holmberg, Umeå University, Medical biosciences/Medical genetics, Umeå , Sweden,

Participating lab: Laurie Ozelius, Massachusetts General Hospital, Boston, USA, previously Icahn School of Medicine at Mount Sinai, New York.

20 000 EUR

The aim of this study is to identify the DYT21 gene using next generation DNA sequencing. The DYT21 gene was recently mapped to chromosome 2q21.1-21.3 using a large North-Swedish family. The dystonia gene in this family is of a mixed type and shows an unusually high penetrance, with as many as 90% of the carriers expressing the phenotype.