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

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The dystonias are rare movement disorders. Despite diverse underlying aetiopathogeneses, 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 neuronaldysfunction on the microcircuit and large-scale network level, leading to the manifestation of dystonia as a common final symptom pathway. Hereditary dystonias offer a unique opportunity to study this pathophysiological path from molecular to brain circuit dysfunction in model systems, but so far most transgenic rodent models lack a convincing dystonic phenotype. Gene environmental interactions in dystonia pathogenesis is discussed in hereditary forms with reduced penetrance. Based on the hypothesis of a “second hit”, we have been able to elicit a dystonialike phenotype in transgenic rodents harbouring the human mutations of TOR1A (DYT1) by exposing the animals to a sensorimotor stressor. These dystonia models are being expanded to THAP1 (DYT6) and GNAL (DYT25) mutations, 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: a) explore disease mechanisms and identify common (and novel) pathophysiological pathways from the molecular to the brain network level using genetically and phenotypically relevant mouse models of genetically divergent dystonias (DYT1, DYT6, DYT25); b) analyse the pathophysiology and disease progression of monogenic and sporadic dystonia in patients by identification of clinical biomarkers; c) support the current clinical diagnosis of dystonia by molecular biomarkers derived from multi-omic approaches comparing mouse tissue with accessible human material from dystonia patients. Multi-omics, fMRI, MEG, TMS, LFP, LTP/LTD, PAS, optogenetics and in-vivo calcium imaging will be used to characterise brain network changes in rodent models and human dystonia. For clinical studies, patients will be recruited from various European countries with the aid of Dystonia Europe and the German Dystonia Registry.