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

肌张力障碍是一种罕见的运动障碍。尽管潜在的病因多种多样，肌张力障碍具有共同的临床表现，运动缺陷是由各种基因缺陷、脑损伤或环境因素引起的脑回路功能障碍引起的，或者可能是特发性的。目前尚不清楚不同的遗传性分子缺陷如何在微回路和大规模网络水平上引起神经元功能障碍，从而导致肌张力障碍作为常见的最终症状途径的表现。遗传性肌张力障碍提供了一个独特的机会，研究这种病理生理学路径从分子到脑回路功能障碍的模型系统，但到目前为止，大多数转基因啮齿动物模型缺乏令人信服的肌张力障碍表型。基因环境的相互作用在肌张力障碍发病机制进行了讨论，在遗传形式与减少的遗传率。基于“第二次打击”的假设，我们已经能够通过将动物暴露于感觉运动应激物来在携带人TOR 1A（DYT 1）突变的转基因啮齿动物中引发肌张力障碍样表型。这些肌张力障碍模型正在扩展到THAP 1（DYT 6）和GNAL（DYT 25）突变，使我们能够辨别与环境触发后肌张力障碍的易感性和发作相关的转录组，代谢和生理CNS改变。EurDyscover联盟结合了欧洲各地在分子神经生物学、细胞和系统病理生理学以及行为和临床神经科学方面的杰出专业知识，旨在：a）探索疾病机制，从分子到大脑网络水平的（和新的）病理生理学途径，使用遗传和表型相关的遗传差异性肌张力障碍小鼠模型（DYT 1，DYT 6，DYT 25）; B）通过鉴定临床生物标志物来分析患者中单基因和散发性肌张力障碍的病理生理学和疾病进展; c）通过将小鼠组织与来自肌张力障碍患者的可获得的人材料进行比较的多组学方法衍生的分子生物标志物来支持肌张力障碍的当前临床诊断。多组学、fMRI、MEG、TMS、LFP、LTP/LTD、PAS、光遗传学和体内钙成像将用于研究啮齿动物模型和人类肌张力障碍中的脑网络变化。对于临床研究，将在欧洲肌张力障碍和德国肌张力障碍登记处的帮助下从欧洲各国招募患者。

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.