EURDYSCOVER : Pathophysiology of dystonia – role of gene-environment interaction and common pathophysiological pathways

The dystonias are rare movement disorders. Despite diverse underlying etiopathogeneses, dystonias share a common clinical presentation, with motor deficits that result from brain circuit dysfunction caused by various gene defects, brain lesions, or environmental factors, or which may emerge idiopathically. It is unclear how different inherited molecular defects cause neuronal dysfunction on the microcircuit and large scale network level, leading to the manifestation of dystonia as a common final symptom pathway. Gene-environmental interaction in dystonia pathogenesis is discussed in hereditary forms with reduced penetrance. Based on the “second hit” hypothesis, we have generated endogenously predisposed DYT1 and DYT12 models with trauma-triggered dystonia-like movements, allowing us to discern transcriptomic, metabolic and physiological CNS alterations related to the predisposition and the onset of dystonia after an environmental trigger. The EurDyscover consortium combines outstanding expertise from across Europe in molecular neurobiology, cellular and system pathophysiology, and behavioural and clinical neurosciences to map the entire disease pathway of dystonia from the molecular to the brain network level in mice and humans and to identify new targets for treatment. Methods such as multi-omic, fMRI, MEG, TMS, LFP, LTP/LTD, PAS, optogenetics and in-vivo calcium imaging to characterise brain network changes in rodent models and human dystonia will be used. For clinical studies, patients will be recruited from various European countries and the German dystonia registry.