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。尽管有不同的潜在发病机制，但口吃困难有一个共同的临床表现，运动障碍是由各种基因缺陷、脑损伤或环境因素引起的脑回路功能障碍所致，或可能特发性出现。目前尚不清楚不同的遗传分子缺陷如何在微电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的表现为常见的最终症状途径。遗传性肌张力障碍为在模型系统中研究从分子到脑回路功能障碍的病理生理途径提供了独特的机会，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。基因环境交互作用在肌张力障碍的发病机制中被讨论为外显性降低的遗传性形式。基于“二次打击”的假设，我们已经能够通过将转基因啮齿动物暴露在感觉运动应激源中，在含有人类TOR1A(DYT1)突变的转基因啮齿动物中诱导出一种Dstonilike表型。这些肌张力障碍模型正在扩展到THAP1(DYT6)和GNAL(DYT25)突变，使我们能够识别与环境触发后肌张力障碍的易感性和发病相关的转录、代谢和生理中枢神经系统的变化。EurDyscover财团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、行为和临床神经科学方面的杰出专业知识，以：a)利用基因分歧型肌张力障碍(DYT1、DYT6、DYT25)的遗传和表型相关小鼠模型，探索疾病机制并确定从分子水平到脑网络层面的常见(和新颖)病理生理学路径；b)通过识别临床生物标志物，分析单基因和散发性肌张力障碍患者的病理生理学和疾病进展；c)通过比较小鼠组织和来自肌张力障碍患者的可获得的人材料，支持目前临床诊断肌张力障碍的分子生物标记物。多组学、fMRI、MEG、TMS、LFP、LTP/LTD、PAS、光遗传学和体内钙成像将用于表征啮齿动物模型和人类肌张力障碍模型的脑网络变化。对于临床研究，将在Dystonia Europe和德国Dystonia注册中心的帮助下，从不同的欧洲国家招募患者。

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.