Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although dysfunction of the basal ganglia, a brain region that mediates movement, is implicated in many forms of dystonia, the underlying mechanisms are unclear. The inherited metabolic disorder DOPA-responsive dystonia is considered a prototype for understanding basal ganglia dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of the neurotransmitter dopamine, which mediates the activity of the basal ganglia. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented and proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated striatal proteins identified in our screen are associated with pathogenic variants that cause inherited disorders with dystonia as a sign in humans suggesting shared mechanisms across many different forms of dystonia.

肌张力障碍的特征是不自主的肌肉收缩，导致令人衰弱的扭转运动和姿势。尽管基底神经节（介导运动的大脑区域）的功能障碍与多种形式的肌张力障碍有关，但其潜在机制尚不清楚。遗传性代谢性疾病多巴反应性肌张力障碍被认为是理解肌张力障碍中基底神经节功能障碍的原型，因为它是由合成神经递质多巴胺所需的基因突变引起的，而多巴胺介导基底神经节的活动。因此，为了揭示与肌张力障碍有关的异常纹状体细胞过程和途径，我们在多巴反应性肌张力障碍的敲入小鼠模型中使用了无偏蛋白质组学方法，已知纹状体在肌张力障碍的表达中发挥核心作用。与对照小鼠相比，多巴反应性肌张力障碍小鼠中鉴定出的 1805 种蛋白质中有 57 种受到差异性调节。大多数差异调节蛋白质与基因本体术语相关，这些术语涉及线粒体或突触功能障碍，其中与线粒体功能相关的蛋白质通常被过度代表，而与突触功能相关的蛋白质在很大程度上被低估。值得注意的是，在我们的筛选中发现的差异调节纹状体蛋白中，近 20% 与导致遗传性疾病的致病变异相关，肌张力障碍是人类的一个标志，表明许多不同形式的肌张力障碍之间存在共同的机制。